Indoline compounds as aldosterone synthase inhibitors

ABSTRACT

This invention relates to indo line compounds of the structural formula I, or their pharmaceutically acceptable salts, wherein the variables are defined herein. The inventive compounds selectively inhibit aldosterone synthase. This invention also provides for pharmaceutical compositions comprising the compounds of Formula I or their salts as well as potentially to methods for the treatment amelioration or prevention of conditions that could be treated by inhibiting aldosterone synthase.

RELATED APPLICATIONS

This application claims benefit of Provisional application U.S. Ser. No.61/710,197, filed Oct. 5, 2012, herein incorporated by reference.

FIELD OF THE INVENTION

The present invention relates indoline compounds, which selectivelyinhibit aldosterone synthase (CYP11B2) with diminished inhibition oraffect on steroid-11-β-hydroxylase (CYP11B1) inhibitors. The inventivecompounds potentially have utility in treating cardiovascular diseasessuch as hypertension or heart failure. The present invention alsorelates to pharmaceutical compositions comprising the inventivecompounds as well as processes for their preparation.

BACKGROUND OF THE INVENTION

Aldosterone is a steroid hormone secreted in the adrenal cortex. Inprimary cells of the distal tubules and collecting ducts of the kidney,aldosterone binding to the mineralocorticoid receptor (MR) results inthe retention of sodium and water and excretion of potassium, which inturn leads to increased blood pressure. Aldosterone also causesinflammation that leads to fibrosis and remodeling in the heart,vasculature and kidney. This inflammation may proceed by MR-dependent aswell as MR-independent mechanisms (Gilbert, K. C. et al., Curr. Opin.Endocrinol. Diabetes Obes., vol. 17, 2010, pp. 199-204).

Mineralocorticoid receptor antagonists (MRAs), such as spironolactoneand eplerenone, have been used previously to block the effects ofaldosterone binding to MR. When given in addition to standard therapiessuch as angiotensin-converting enzyme (ACE) inhibitors and loopdiuretics, the nonselective MRA spironolactone and the selective MRAeplerenone significantly reduced morbidity and mortality in patientswith heart failure or myocardial infarction (Pitt, B. et al., New Engl.J. Med., vol. 341, 1999, pp. 709-717; Pitt, B. et al., New Engl. J.Med., vol. 348, 2003, pp. 1382-1390). However, the nonselective MRAspironolactone can also bind to and act at other steroid receptors, andas a consequence its use is associated with sexual side effects such asgynecomastia, dysmenorrhoea and impotence (Pitt, B. et al., New Engl. J.Med., vol. 341, 1999, pp. 709-717; MacFadyen, R. J. et al., Cardiovasc.Res., vol. 35, 1997, pp 30-34; Soberman, J. E. et al., Curr. Hypertens.Rep., vol. 2, 2000, pp 451-456). Additionally, both spironolactone andeplerenone are known to cause elevated plasma potassium levels(hyperkalemia) and elevated aldosterone levels.

An alternative method of blocking the effects of aldosterone is toinhibit its biosynthesis. CYP11B2 is a mitochondrial cytochrome P450enzyme that catalyzes the final oxidative steps in the conversion of11-deoxycorticosterone, a steroidal precursor, to aldosterone (Kawamoto,T. et al., Proc. Natl. Acad. Sci. USA, vol. 89, 1992, pp. 1458-1462).Compounds that inhibit CYP11B2 should thus inhibit the formation ofaldosterone. Such compounds, particularly those of nonsteroidalstructure, should provide the beneficial effects of MRAs, without theadverse effects derived from steroid receptor binding or MR-independentinflammatory pathways. The art has recognized that reducing aldosteronelevels by inhibiting aldosterone synthase could represent a newpharmaceutical strategy that might be useful in treating a disorder ordisease characterized by increased stress hormone levels and/ordecreased androgen hormone levels in a patient (WO2011/088188 toNovartis). Compounds possessing this activity might be expected to treatdisease states such as heart failure, cachexia, acute coronary syndrome,Cushing's syndrome or metabolic syndrome.

CYP11B1 is a related enzyme that catalyzes the formation ofglucocorticoids, such as cortisol, an important regulator of glucosemetabolism. Because human CYP11B2 and CYP11B1 are greater than 93%homologous, it is possible for nonselective compounds to inhibit bothenzymes (Kawamoto, T. et al., Proc. Natl. Acad. Sci. USA, vol. 89, 1992,pp 1458-1462; Taymans, S. E. et al., J. Clin. Endocrinol. Metab., vol.83, 1998, pp 1033-1036). It would be preferable, however, fortherapeutic agents to selectively inhibit CYP11B2 and the formation ofaldosterone with diminished inhibition of, or affect on, CYP11B1 and theproduction of cortisol.

WO 2009/135651 to Elexopharm describes6-pyridin-3yl-3,4,-dihydro-1H-quinolin-2-one derivatives as beingCYP11B2 inhibitors. Two compounds described therein are lactamderivatives of the formula:

Structurally similar lactam and thiolactam compounds are disclosed byLucas et al., J. Med. Chem. 2008, 51, 8077-8087; those compounds aresaid to be potential inhibitors of CYP11B2. Lucas et al. in J. Med.Chem. 2011, 54, 2307-2309 describes certain pyridine substituted3,4-dihydro-1H-quinolin-2-ones as being highly potent as selectiveinhibitors of CYP11B2. An abstract of a thesis reports that a series ofnovel heterocyclic-substituted4,5-dihydro-[1,2,4]triazolo[4,3a]quinolones was evaluated for itsaldosterone synthase activity; one of the compounds is reported asexhibiting excellent selectivity of CYP11B2 over CYP11B1.

Benzimidazole derivatives are known in the art to treat various diseasestates. For example, U.S. Pat. No. 6,897,208 to Aventis Pharmaceuticalsdescribes compounds of the formula:

wherein R¹ is an optionally substituted aryl or heteroaryl group and A₅is H or alkyl. These compounds are said to be kinase inhibitors. Otherbenzimidazoles derivatives are known in the art. For example,WO2002/46168 A1 to AstraZeneca describes benzimidazoles derivatives thatare useful in the treatment or prophylaxis of Alzheimer's disease,anxiety disorders, depressive disorders, osteoporosis, cardiovasculardisease, rheumatoid arthritis or prostate cancer. US2007/0270420 A1 toVertex Pharmaceuticals describes benzimidazole compounds that are usefulof inhibitors of GSK-3 and Lck protein kineases. WO2012/012478 to Merckdescribes benzimidazole compounds that are effective at selectivityinhibiting CYP11B2. Other benzimidazole derivatives are described in US2009/0018124 A1, WO2004/082638 A1, WO2008/073451 A1 and US 2005/0272756A1.

Novartis in US 2010/0261698 A1 describes indole derivatives of theformula:

Novartis indicates that these compounds inhibit aldosterone synthase andmay be useful in the treatment of disease states such as heart failureand hypertension. In WO2010/130,796 A1 and WO2011/061168, Novartisdiscloses aryl-pyridine derivatives that are said to inhibit aldosteronesynthase.

US 2009/0221591 A1 to Universitat des Saarlandes also disclosescompounds that inhibit CYP11B1 and CYP11B2. WO 2009/135651 toUniversitat des Saarlandes teaches that compounds of the formula:

possess the ability to inhibit aldosterone synthase.

WO1999/400094 Bayer AG discloses oxazolidinones with azol-containingtricycles as having antibacterial activity.

U.S. Pat. No. 7,381,825 to Takeda describes histone deacetylaseinhibitors of the formula

Z-Q-L-M

where Q is a substituted or unsubstituted aromatic ring, L is asubstituent providing between 0-10 atoms separation between M and theremainder of the compound, M is a substituent capable of complexing witha deacetylase catalytic site and/or metal ion, and Z is list of bicyclicgroups, including, but not limited to:

where X is CR₁₂ or N. These compounds are said to be useful in treatingcell-proliferative diseases such as, for example, leukemia, melanoma,bladder cancer, etc.

FR 2 530 246 to Delalande SA describes pyridyl-substituted indolinecompounds of the formula:

where R may be groups such as H, —COCH₃ and benzyl, as possessingcardiovascular utility.

Other heterocyclic substituted indoline derivatives are described in WO2011/119663 to GlaxoSmithKline, WO1998/46605 and WO 2000/23444 to AbbottLaboratories, WO 2011/095196 to Merck GmbH, U.S. Pat. No. 7,872,031 toVertex Pharmaceuticals. None of the compounds disclosed these publishedapplications is taught to be inhibitors of aldosterone synthase.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides for novelindoline compounds, which are inhibitors of CYP11B2, or metabolites,stereoisomers, salts, solvates or polymorphs thereof, processes ofpreparing such compounds, pharmaceutical compositions comprising one ormore such compounds, processes of preparing pharmaceutical compositionscomprising one or more such compounds and potentially methods oftreatment, inhibition or amelioration of one or more disease statesassociated with inhibiting CYP11B2 by administering an effective amountat least one of the inventive indoline compounds to a patient in needthereof.

In one aspect, the present application discloses a compound or apharmaceutically acceptable salt, metabolite, solvate, prodrug orpolymorph of said compound, said compound having the general structureshown in Formula I

wherein:

R¹ is —C(O)R⁷; —C(O)OR⁷; —C(O)N(R¹¹)(R¹²); —C(S)R⁷; —S(O)₂R⁷; alkylwhich is optionally substituted on or more times (e.g., 1 to 4 times) byhalogen; cycloalkyl, which is optionally substituted one or more times(e.g., 1 to 4) by halogen, alkyl or haloalkyl; aryl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; arylalkyl,wherein the aryl ring is optionally substituted one or more times (e.g.,1 to 4 times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; heteroaryl optionally substituted one ormore times (e.g., 1 to 4 times) by halogen, alkyl, haloalkyl,cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or arylalkylcarbonyl,wherein the aryl ring is optionally substituted one or more times byhalogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;

R² is H; halogen; —CN; —OR⁷; —N(R¹⁰)C(O)R⁷; —NR¹¹R¹²; —C(O)R⁷;—C(O)N(R¹¹)(R¹²); —N(R¹⁰)C(O)—R⁷; —C(O)OR⁷; —OC(O)R⁷; SO₂N(R¹¹)(R¹²);—N(R¹⁰)SO₂—R⁷; —S(O)_(m)—R⁷; alkyl optionally substituted one or moretimes (e.g., 1 to 4 times) by halogen, —OR⁷, NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; cycloalkyl optionally substituted one ormore times (e.g., 1 to 4 times) by halogen, alkyl, haloalkyl, —OR⁷,—NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionally substitutedone or more times (e.g., 1 to 4 times) by halogen, alkyl, haloalkyl,—OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; aryl optionally substituted one or moretimes (e.g., 1 to 4 times) by halogen, alkyl, haloalkyl, cycloalkyl,—OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷,—OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or heteroaryloptionally substituted one or more times (e.g., 1 to 4 times) byhalogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;

R³ is H; halogen; —CN; —OR⁷; —N(R¹⁰)C(O)R⁷; —NR¹¹R¹²; —C(O)R⁷;—C(O)N(R¹¹)(R¹²); —N(R¹⁰)C(O)—R⁷; —C(O)OR⁷; —OC(O)R⁷; —SO₂N(R¹¹)(R¹²);—N(R¹⁰)SO₂—R⁷; —S(O)_(m)—R⁷; alkyl optionally substituted one or moretimes (e.g., 1 to 4 times) by halogen, —OR⁷, NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; cycloalkyl optionally substituted one ormore times (e.g., 1 to 4 times) by halogen, alkyl, haloalkyl, —OR⁷,—NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionally substitutedone or more times (e.g., 1 to 4 times) by halogen, alkyl, haloalkyl,—OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; aryl optionally substituted one or moretimes (e.g., 1 to 4 times) by halogen, alkyl, haloalkyl, cycloalkyl,—OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷,—OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or heteroaryloptionally substituted one or more times (e.g., 1 to 4 times) byhalogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;

R⁴ is H; halogen; —CN; alkyl optionally substituted one or more times(e.g., 1 to 4 times) by halogen or cycloalkyl optionally substitutedonce or twice by alkyl or halogen; or cycloalkyl optionally substitutedonce or twice by alkyl or halogen;

R⁵ is H; halogen; —CN; alkyl optionally substituted one or more times(e.g., 1 to 4 times) by halogen or cycloalkyl optionally substitutedonce or twice by alkyl or halogen; or cycloalkyl optionally substitutedonce or twice by alkyl or halogen;

R⁶ is H; halogen; —CN; alkyl optionally substituted one or more times(e.g., 1 to 4 times) by halogen or cycloalkyl optionally substitutedonce or twice by alkyl or halogen; or cycloalkyl optionally substitutedonce or twice by alkyl or halogen;

R⁷ is independently H; alkyl optionally substituted one or more times(e.g., 1 to 4 times) by halogen, —OR¹⁰, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰,—C(O)N(R⁸)(R⁹), —C(O)R¹⁰, —C(O)OR¹⁰ or —S(O)_(m)—R¹⁰; cycloalkyloptionally substituted one or more times (e.g., 1 to 4 times) byhalogen, alkyl, haloalkyl, —OR¹⁰, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰,—C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or —S(O)_(m)—R¹⁰; aryl optionally substitutedone or more times (e.g., 1 to 4 times) by halogen, alkyl, haloalkyl,cycloalkyl, —OR¹⁰, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰, —C(O)N(R⁸)(R⁹),—C(O)R¹⁰, —C(O)OR¹⁰—OC(O)R¹⁰, or —S(O)_(m)—R¹⁰; or heteroaryl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, cycloalkyl, —OR¹⁰, —NR⁸R⁹, —CN, —N(R⁹)C(O)R¹⁰,—C(O)N(R⁸)(R⁹), —C(O)R¹⁰, —C(O)OR¹⁰—OC(O)R¹⁰ or —S(O)_(m)—R¹⁰;

R⁸ is independently H or alkyl;

R⁹ is independently H or alkyl;

-   -   or R⁸ and R⁹ are joined together with the nitrogen to which they        are attached form a saturated 5- to 7-membered heterocyclic        ring;

R¹⁰ is independently H, alkyl or haloalkyl;

R¹¹ is independently H; alkyl optionally substituted one or more times(e.g., 1 to 4 times) by halogen, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷ or —S(O)_(m)—R⁷; cycloalkyl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁸ or—S(O)_(m)—R⁸; aryl optionally substituted one or more times (e.g., 1 to4 times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹)N(R¹⁰)C(O)(R⁷), —C(O)N(R⁷)(R⁸), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷ or—S(O)_(m)—R⁷; heterocycloalkyl optionally substituted one or more times(e.g., 1 to 4 times) by halogen, alkyl, haloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷ or—S(O)_(m)—R⁷; or heteroaryl optionally substituted one or more times(e.g., 1 to 4 times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷,—CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷or —S(O)_(m)—R⁷;

R¹² is independently H; alkyl optionally substituted one or more times(e.g., 1 to 4 times) by halogen, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷ or —S(O)_(m)—R⁷; cycloalkyl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁸ or—S(O)_(m)—R⁸; aryl optionally substituted one or more times (e.g., 1 to4 times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁷)(R⁸), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷ or—S(O)_(m)—R⁷; heterocycloalkyl optionally substituted one or more times(e.g., 1 to 4 times) by halogen, alkyl, haloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷ or—S(O)_(m)—R⁷; or heteroaryl optionally substituted one or more times(e.g., 1 to 4 times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷,—CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷or —S(O)_(m)—R⁷;

-   -   or R¹¹ and R¹² are joined together with the nitrogen to which        they are attached form a saturated 5- to 7-membered heterocyclic        ring;

R¹³ is H; halogen; —CN; —OR⁷; —NR¹¹R¹²; —N(R¹⁰)C(O)R⁷; —C(O)N(R¹¹)(R¹²);—C(O)R⁷; —C(O)OR⁷; —OC(O)R⁷; —SO₂N(R¹¹)(R¹²); —N(R¹⁰)SO₂—R⁷;—S(O)_(m)—R⁷; alkyl optionally substituted one or more times (e.g., 1 to4 times) by halogen, —OR⁷, —NR⁸R⁹, —CN, —N(R¹¹)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷, or —S(O)_(m)—R⁷;cycloalkyl optionally substituted one or more times (e.g., 1 to 4 times)by halogen, alkyl, haloalkyl, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;aryl optionally substituted one or more times (e.g., 1 to 4 times) byhalogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷),—C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionally substitutedone or more times (e.g., 1 to 4 times) by halogen, alkyl, haloalkyl,cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or monocyclic heteroaryloptionally substituted one or more times (e.g., 1 to 4 times) byhalogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;

R¹⁴ is H; halogen; —CN; —OR⁷; —NR¹¹R¹²; —N(R¹⁰)C(O)R⁷; —C(O)N(R¹¹)(R¹²);—C(O)R⁷; —C(O)OR⁷; —OC(O)R⁷; —SO₂N(R¹¹)(R¹²); —N(R¹⁰)SO₂—R⁷;—S(O)_(m)—R⁷; alkyl optionally substituted one or more times (e.g., 1 to4 times) by halogen, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or—S(O)_(m)—R⁷; cycloalkyl optionally substituted one or more times (e.g.,1 to 4 times) by halogen, alkyl, haloalkyl, —OR⁷, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or—S(O)_(m)—R⁷; aryl optionally substituted one or more times (e.g., 1 to4 times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁷)(R⁸), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷,—SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; heterocycloalkyloptionally substituted one or more times (e.g., 1 to 4 times) byhalogen, alkyl, haloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;or monocyclic heteroaryl optionally substituted one or more times (e.g.,1 to 4 times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;

-   -   or R¹³ and R¹⁴ are joined together to form a 5-7 membered        carbocyclic or heterocyclic ring that is fused to the pyridyl        ring to which R¹³ and R¹⁴ are attached, wherein the ring formed        by R¹³ and R¹⁴ is optionally substituted by 1 to 3 R¹⁵;

R¹⁵ is independently H; halogen; —CN; —OR⁷; —C(O)N(R⁸)(R⁹); —C(O)R⁷;—C(O)OR⁷; —OC(O)R⁷; —SO₂N(R⁸)(R⁹); —N(R¹⁰)SO₂—R⁷; —S(O)_(m)—R⁷; alkyloptionally substituted one or more times (e.g., 1 to 4 times) byhalogen, —OR⁷, —NR⁸R⁹, —CN, —N(R¹¹)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷,—C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)S(O)₂—R⁷, or —S(O)_(m)—R⁷;cycloalkyl optionally substituted one or more times (e.g., 1 to 4 times)by halogen, alkyl, haloalkyl, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁸, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;aryl optionally substituted one or more times (e.g., 1 to 4 times) byhalogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹,—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁸)(R⁹), —C(O)R⁷—C(O)OR⁷, —OC(O)R⁷,—SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷, or —S(O)_(m)—R⁷; heterocycloalkyloptionally substituted one or more times (e.g., 1 to 4 times) byhalogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or heteroaryl optionally substituted oneor more times (e.g., 1 to 4 times) by halogen, alkyl, haloalkyl,cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷,—C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;

is a single or double bond; and

m is 0, 1 or 2;

provided that when R¹ is —C(O)alkyl, R⁵, R⁶ R¹³ and R¹⁴ cannot all behydrogen at the same time

and further provided that monocyclic heteroaryl cannot be a tetrazolering.

Another aspect of the present invention is pharmaceutical compositionscomprising a therapeutically effective amount of at least one compoundof Formula I or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.

Another aspect of the present invention is pharmaceutical compositionscomprising a therapeutically effective amount of at least one compoundof Formula I or a pharmaceutically acceptable salt thereof, atherapeutically effective amount of at least one additional therapeuticagent and a pharmaceutically acceptable carrier.

Another aspect of the present invention potentially is the prevention ofone or more disease states associated with inhibiting CPY11B2 byadministering an effective amount of at least one of the inventiveimidazopyridyl compounds to a patient in need thereof.

It is further contemplated that the combination of the invention couldbe provided as a kit comprising in a single package at least onecompound of Formula I or a pharmaceutically acceptable salt thereof in apharmaceutical composition, and at least one separate pharmaceuticalcomposition, such as, for example a separate pharmaceutical compositioncomprising a therapeutic agent.

The compounds of the present invention could be useful in the treatment,amelioration or prevention of one or more conditions associated withinhibiting CYP11B2 by administering a therapeutically effective amountof at least one compound of Formula I or a pharmaceutically acceptablesalt thereof to a mammal in need of such treatment. Conditions thatcould be treated or prevented by inhibiting CYP11B2 includehypertension, heart failure such as congestive heart failure, diastolicdysfunction, left ventricular diastolic dysfunction, heart failure(including congestive heart failure), diastolic dysfunction, leftventricular diastolic dysfunction, diastolic heart failure, systolicdysfunction, hypokalemia, renal failure (including chronic renalfailure), restenosis, syndrome X, nephropathy, post-myocardialinfarction, coronary heart diseases, increased formation of collagen,fibrosis and remodeling following hypertension and endothelialdysfunction, cardiovascular diseases, renal dysfunction, liver diseases,vascular diseases, cerebrovascular diseases, retinopathy, neuropathy,insulinopathy, endothelial dysfunction, ischemia, myocardial andvascular fibrosis, myocardial necrotic lesions, vascular damage,myocardial necrotic lesions, vascular damage, myocardial infarction,left ventricular hypertrophy, cardiac lesions, vascular wallhypertrophy, endothelial thickening or fibrinoid necrosis of coronaryarteries.

The compounds of the present invention also might be useful in treatingone or more conditions characterized by increased stress hormone levelsand/or decreased androgen hormone levels in a mammal by administering atherapeutically effective amount of at least one compound of Formula Ior a pharmaceutically acceptable salt thereof to a mammal in need ofsuch treatment. Conditions characterized by increased stress hormonelevels and/or decreased androgen hormone levels in a mammal include, forexample, heart failure (e.g., acute heart failure, acute decompensatedheart failure, chronic heart failure, chronic heart failure withimpaired exercise tolerance or chromic heart failure with muscleweakness), cachexia (e.g., cardiac cachexia, COPD-induced cachexia,cirrhosis-induced cachexia, tumor-induced cachexia or viral(HIV)-induced cachexia), acute coronary syndrome, Cushing's syndrome ormetabolic syndrome.

Another aspect of the present invention could be the use of a compoundof Formula I or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for the treatment, amelioration orprevention of one or more conditions associated with inhibiting CYP11B2in a patient.

Another aspect of the present invention could be the use of a compoundof Formula I or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for the treatment, amelioration orprevention of one or more conditions associated with inhibiting CYP11B2in a patient.

This invention further relates to process for the preparation of thecompounds of Formula I or their pharmaceutically acceptable salts.Moreover, this invention also relates to the use of the compounds ofFormula I or their pharmaceutically acceptable salts to validate invitro assays, such as, for example the V79-Human-CYP11B2 andV79-Human-CYP11B1 discussed later in the application.

These and other objectives will be evident from the description of theinvention contained herein.

DETAILED DESCRIPTION

In an embodiment, the present invention provides compounds representedby structural Formula I or pharmaceutically acceptable salt thereof,wherein the various moieties are as described as above.

Another embodiment of the present invention is compounds of Formula I ortheir pharmaceutically acceptable salts wherein

is a single bond.

Another embodiment of the present invention is compounds of Formula I ortheir pharmaceutically acceptable salts wherein

is a double bond.

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of Formula I represented by structuralFormula II

wherein R¹, R⁶, R¹³ and R¹⁴ are as defined in Formula I.

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of Formula I represented by structuralFormula III

wherein R¹, R⁵, R¹³ and R¹⁴ are as defined in Formula I.

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of Formula I represented by structuralFormula IV

wherein R¹, R¹³ and R¹⁴ are as defined in Formula I.

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of Formula I represented by structuralFormula V

wherein R¹, R⁶ and R¹⁵ are as defined in Formula I and a is 0, 1 or 2.

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of Formula V, wherein R¹, R², R³ andare as defined in Formula I and a is 0 (i.e., R¹⁵ is absent), or whereina is 1 or 2 and R¹⁵ is alkyl or halo.

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through V, wherein R¹ is —C(O)R⁷, —C(O)OR⁷, or —C(O)N(R¹¹)(R¹²),wherein R⁷, R¹¹ or R¹² is as defined as in Formula I.

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through V, wherein R¹ is arylalkylcarbonyl, wherein the aryl ring(e.g., phenyl) is optionally substituted one or more times by halogen,alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷,wherein R⁷, R⁸, R⁹, R¹⁰ and m are as defined in Formula I (e.g., alkyl).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through V, wherein R¹ is —C(O)R⁷, —C(O)OR⁷, or —C(O)N(R¹¹)(R¹²),wherein R⁷ is alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,iso-butyl, sec-butyl, tert-butyl) or aryl (e.g., phenyl) or aryl (e.g.phenyl) substituted one or twice by halogen, —OR⁷ (where R⁷ is H, alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl) or haloalkyl (e.g., —CF₃)) or haloalkyl (e.g., —CF₃); R¹¹ isH; and R¹² is alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,iso-butyl, sec-butyl, tert-butyl) or aryl (e.g., phenyl) or aryl (e.g.phenyl) substituted one or twice by halogen, —OR⁷ (where R⁷ is H, alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl) or haloalkyl (e.g., —CF₃)) or haloalkyl (e.g., —CF₃).

Another embodiment of the present invention is compound or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through V wherein R¹ is —C(O)R⁷ and R⁷ is or heteroaryl (e.g., athienyl, furanyl or pyrazolyl ring).

Another embodiment of the present invention is compound or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through V wherein R¹ is —C(S)R⁷ and R⁷ is alkyl.

Another embodiment of the present invention is compound or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through V wherein R¹ is benzoyl which is optionally substituted onceor twice by alkyl (e.g., methyl or ethyl), halogen or alkoxy (e.g.,methoxy or ethoxy), or haloalkyl (e.g., —CF₃).

Another embodiment of the present invention is compound or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through V wherein R², R³ and R⁴ are hydrogen.

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiment of Formulae Ior III above wherein R⁵ is halogen (e.g., —F or —Cl).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiment of FormulaeI, II, or V above wherein R⁶ is halogen (e.g., —F or —Cl).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through IV above wherein R¹⁴ is H, halogen (e.g., —F or —Cl); —CN;—OR⁷ (where R⁷ is H, alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, iso-butyl, sec-butyl, or tert-butyl)); alkyl (e.g., methyl orethyl) or haloalkyl (e.g., —CF₃).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through IV above wherein R¹⁴ is H, alkyl or haloalkyl.

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through IV above where R¹³ is H, halogen (e.g., —F or —Cl), —CN, alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl), —OR⁷ (where R⁷ is H, alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl) or haloalkyl(e.g., —CF₃)), haloalkyl (e.g., —CF₃) or phenyl optionally substitutedby halogen, —OR⁷ (where R⁷ is H, alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl) or haloalkyl(e.g., —CF₃)) or haloalkyl (e.g., —CF₃)).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through IV above where R¹³ is H, halogen (e.g., —F or —Cl), —CN, alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl, sec-butylor tert-butyl), —OR⁷ (where R⁷ alkyl, phenyl or phenyl substituted oneor twice by halogen, —OH, alkoxy or haloalkoxy), haloalkyl (e.g., —CF₃)or phenyl optionally substituted once or twice by halogen (e.g., —F or—Cl) or haloalkyl (e.g., CF₃).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts thereof of any of the embodiments ofFormula I through IV described above where R¹⁴ is H, alkyl (e.g., methylor ethyl) or haloalkyl (e.g., —CF₃) and R¹³ is H, halogen (e.g., —F or—Cl), —CN, alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,iso-butyl, sec-butyl or tert-butyl), —OR⁷ (where R⁷ is H, alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl, sec-butyl, ortert-butyl), or haloalkyl (e.g., —CF₃)), haloalkyl (e.g., —CF₃) orphenyl optionally substituted by halogen, —OR⁷ (where R⁷ is H, alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl, sec-butylor tert-butyl) or haloalkyl (e.g., —CF₃)) or haloalkyl (e.g., —CF₃).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts thereof of any of the embodiments ofFormula I through IV described above where R¹⁴ is H or alkyl (e.g.,methyl or ethyl) and R¹³ is CN, —C(O)-alkyl (e.g., acetyl), alkoxy(e.g., methoxy or ethoxy), hydroxyl-substituted alkyl or phenyl.

Another embodiment of the present inventions is compounds or theirpharmaceutically acceptable salts thereof of any of the embodiments ofFormula I through IV described above or their pharmaceuticallyacceptable salts thereof where R¹⁴ is H, alkyl (e.g., methyl or ethyl)or haloalkyl (e.g., —CF₃) and R¹³ is a group of the formula:

-   -   where:        -   R^(a) is H, OH, or —C₁-C₃-alkyl optionally substituted with            1 to 3-F (e.g. CF₃);        -   R^(b) is H, —OH, or —C₁-C₃-alkyl optionally substituted with            1 to 3-F (e.g. CF₃);        -   R^(c) is —C₁-C₃-alkyl optionally substituted with 1 to 3-F            (e.g. CF₃), is —OC₁-C₃-alkyl, —N(H)S(O)₂—C₁-C₃-alkyl,            optionally substituted with 1 to 3-F (e.g. —CF₃),            —N(H)C(O)C₁-C₃-alkyl, optionally substituted with 1 to 3-F            (e.g. —CF₃).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of Formula I represented by structuralFormula VI

wherein R¹ is —C(O)R⁷, —C(S)R⁷, or benzoyl, which is optionallysubstituted once or twice by alkyl, halogen, alkoxy or haloalkyl; R⁷ isalkyl (e.g., methyl or ethyl), haloalkyl, cycloalkyl (e.g. cyclopropyl),phenyl, phenyl substituted once or twice by halogen or alkoxy, orheteroaryl (e.g., thienyl); R¹³ is H, —CN, alkoxy (e.g., methoxy orethoxy), hydroxy-substituted alkyl, halogen, phenyl or —C(O)-alkyl(e.g., acetyl); and R¹⁴ is H, alkyl or halogen.

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of Formula I represent by Formula VII

wherein R¹ is —C(O)R⁷, —C(S)R⁷, or benzoyl, which is optionallysubstituted once or twice by alkyl, halogen, alkoxy or haloalkyl; R⁷ isalkyl (e.g., methyl or ethyl), haloalkyl, cycloalkyl (e.g. cyclopropyl),phenyl, phenyl substituted once or twice by halogen or alkoxy; a is 0(i.e., R¹⁵ is absent), or wherein a is 1 or 2 and R¹⁵ is alkyl or halo.

Another embodiment of the invention is the following compounds or theirpharmaceutically acceptable salts:

-   1-propanoyl-5-pyridin-3-yl-2,3-dihydro-1H-indole;-   1-(3-chloropropanoyl)-5-pyridin-3-yl-2,3-dihydro-1H-indole;-   1-(cyclopropylcarbonyl)-5-pyridin-3-yl-2,3-dihydro-1H-indole;-   1-[(4-fluorophenyl)carbonyl]-5-pyridin-3-yl-2,3-dihydro-1H-indolel-[(4-fluorophenyl)carbonyl]-5-pyridin-3-yl-2,3-dihydro-1H-indole;-   1-[(4-methoxyphenyl)carbonyl]-5-pyridin-3-yl-2,3-dihydro-1H-indole;-   1-(phenylacetyl)-5-pyridin-3-yl-2,3-dihydro-1H-indole;-   5-pyridin-3-yl-1-(thiophen-2-ylcarbonyl)-2,3-dihydro-1H-indole;-   4-(1-acetyl-2,3-dihydro-1H-indol-5-yl)isoquinoline;-   4-(1-propanoyl-2,3-dihydro-1H-indol-5-yl)isoquinoline;-   4-[1-(2-methylpropanoyl)-2,3-dihydro-1H-indol-5-yl]isoquinoline;-   4-[1-(cyclopropylcarbonyl)-2,3-dihydro-1H-indol-5-yl]isoquinoline;-   1-(5-(pyridin-3-yl)indolin-1-yl)ethanethione;-   1-acetyl-5-pyridin-3-yl-1H-indole;-   4-(1-acetyl-1H-indol-5-yl)isoquinoline;-   1-acetyl-5-(5-fluoropyridin-3-yl)-2,3-dihydro-1H-indole;-   5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)pyridine-3-carbonitrile;-   1-acetyl-5-(5-methoxypyridin-3-yl)-2,3-dihydro-1H-indole;-   1-[5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)pyridin-3-yl]ethanone;-   1-[5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)pyridin-3-yl]ethanol;-   1-acetyl-5-(5-phenylpyridin-3-yl)-2,3-dihydro-1H-indole; or-   1-acetyl-5-(4-methylpyridin-3-yl)-2,3-dihydro-1H-indole.

Another embodiment of the invention is the following compounds or theirpharmaceutically acceptable salts:

-   1-(7-chloro-5-(5-fluoropyridin-3-yl)indolin-1-yl)-2,2,2-trifluoroethanone;    or-   2,2,2-trifluoro-1-(7-fluoro-5-(5-fluoropyridin-3-yl)indolin-1-yl)ethanone.

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Mammal” means humans and other mammalian animals.

The following definitions apply regardless of whether a term is used byitself or in combination with other terms, unless otherwise indicated.Therefore, the definition of “alkyl” applies to “alkyl” as well as the“alkyl” portions of “hydroxyalkyl”, “haloalkyl”, “alkoxy”, etc.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched.

“Halo” refers to fluorine, chlorine, bromine or iodine radicals.Examples are fluoro, chloro or bromo.

“Halogen” means fluorine, chlorine, bromine, or iodine.

“Haloalkyl” means a halo-alkyl-group in which the alkyl group is aspreviously described. The bond to the parent moiety is through thealkyl. Non-limiting examples of suitable haloalkyl groups includefluoromethyl, difluoromethyl, —CH₂CF₃, —CH₂CHF₂—CH₂CH₂F, or an alkylgroup with one or more terminal carbons tri-substituted with a halogen(e.g., —F) such as, for example —C₁-C₃alkyl-CF₃, —CH(CH₃)(CF₃), CH(CF₃)₂and the like.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and the like. Non-limiting examples of suitable multicycliccycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like, aswell as partially saturated species such as, for example, indanyl,tetrahydronaphthyl and the like.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. Non-limiting examples of suitable aryl groups includephenyl, naphthyl, indenyl, tetrahydronaphthyl and indanyl.

“Heterocycloalkyl” means a non-aromatic saturated monocyclic ormulticyclic ring system comprising about 3 to about 10 ring atoms,preferably about 5 to about 10 ring atoms, in which one or more of theatoms in the ring system is an element other than carbon, for examplenitrogen, oxygen or sulfur, alone or in combination. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclyls contain about 5 to about 6 ring atoms. Theprefix aza, oxa or thia before the heterocycloalkyl root name means thatat least a nitrogen, oxygen or sulfur atom respectively is present as aring atom. Any —NH in a heterocycloalkyl ring may exist protected suchas, for example, as an —N(Boc), —N(CBz), —N(Tos) group and the like;such protections are also considered part of this invention. Thenitrogen or sulfur atom of the heterocycloalkyl ring can be optionallyoxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.Non-limiting examples of suitable monocyclic heterocycloalkyl ringsinclude piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,3-dioxanyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiopyranyl, oxetanyl,tetrahydrothiophenyl, lactam, lactone, and the like.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination, provided that the rings do not include adjacent oxygenand/or sulfur atoms. N-oxides of the ring nitrogens are also included,as well as compounds wherein a ring nitrogen is substituted by an alkylgroup to form a quaternary amine. Preferred heteroaryls contain about 5to about 6 ring atoms. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. Non-limitingexamples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl,thienyl, pyrimidinyl, pyridone (including N-substituted pyridones),isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, oxadiazolyl,tetrazolyl, pyrimidyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,oxindolyl, naphthyridyl (e.g., 1, 5 or 1,7), pyrido[2,3]imidazolyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofuranyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzoxazolyl, benzothiazolyl, pyridopyrimidinyl,7-azaindolyl and the like. The term “heteroaryl” also refers topartially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like. All positionalisomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl.

It should be noted that in heterocycloalkyl ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

When R¹³ and R¹⁴ are joined together to form a 5-7 membered carbocyclicring that is fused to the pyridyl ring to which R¹³ and R¹⁴ areattached, “carbocyclic” means a cycloalkyl, aryl or partiallyunsaturated ring composed of 5-7 carbon atoms wherein two of the carbonsare shared between the fused rings. When R¹³ and R¹⁴ are joined togetherto form a 5-7 membered heterocyclic ring that is fused to the pyridylring to which R¹³ and R¹⁴ are attached, “heterocyclic” means a fullysaturated, partially saturated or aromatic ring composed of carbon atomsand one, two or three heteroatoms selected from N, S, or O, wherein twoof the carbons are shared between the fused rings. Representative ringinclude:

When a moiety can be optionally substituted, it means that each carbonand heteroatom (when present) available for substitution in the givenmoiety may be independently unsubstituted or substituted with specifiednumber of substituents that are the same or different at each occurrenceand which result in the creation of a stable structure as is understoodto be reasonable by one skilled in the art.

Unless expressly depicted or described otherwise, variables depicted ina structural formula with a “floating” bond, such as R¹⁵ in structuralFormula V, are permitted on any available carbon atom in the ring towhich each is attached.

When R⁸ and R⁹ or R¹¹ and R¹² together with the nitrogen to which theyare attached form a saturated 5- to 7-membered heterocyclic ring, thismeans a saturated heterocyclic ring composed of, in addition to the onenitrogen atom, carbon atoms and optionally one additional heteroatomselected from N, S or O. Representative examples include:

It should also be noted that tautomeric forms such as, for example, themoieties:

are considered equivalent in certain embodiments of this invention.

The present invention encompasses all stereoisomeric forms of thecompounds of Formula I. Centers of asymmetry that are present in thecompounds of Formula I can all independently of one another have (R)configuration or (S) configuration. When bonds to the chiral carbon aredepicted as straight lines in the structural Formulas of the invention,it is understood that both the (R) and (S) configurations of the chiralcarbon, and hence both enantiomers and mixtures thereof, are embracedwithin the Formula. Similarly, when a compound name is recited without achiral designation for a chiral carbon, it is understood that both the(R) and (S) configurations of the chiral carbon, and hence individualenantiomers and mixtures thereof, are embraced by the name. Theproduction of specific stereoisomers or mixtures thereof may beidentified in the Examples where such stereoisomers or mixtures wereobtained, but this in no way limits the inclusion of all stereoisomersand mixtures thereof from being within the scope of this invention.

The invention includes all possible enantiomers and diastereomers andmixtures of two or more stereoisomers, for example mixtures ofenantiomers and/or diastereomers, in all ratios. Thus, enantiomers are asubject of the invention in enantiomerically pure form, both aslevorotatory and as dextrorotatory antipodes, in the form of racematesand in the form of mixtures of the two enantiomers in all ratios. In thecase of a cis/trans isomerism the invention includes both the cis formand the trans form as well as mixtures of these forms in all ratios. Thepreparation of individual stereoisomers can be carried out, if desired,by separation of a mixture by customary methods, for example bychromatography or crystallization, by the use of stereochemicallyuniform starting materials for the synthesis or by stereoselectivesynthesis. Optionally, a derivatization can be carried out before aseparation of stereoisomers. The separation of a mixture ofstereoisomers can be carried out at an intermediate step during thesynthesis of a compound of Formula I or it can be done on a finalracemic product. Absolute stereochemistry may be determined by X-raycrystallography of crystalline products or crystalline intermediateswhich are derivatized, if necessary, with a reagent containing astereogenic center of known configuration. Where compounds of thisinvention are capable of tautomerization, all individual tautomers aswell as mixtures thereof are included in the scope of this invention.The present invention includes all such isomers, as well as salts,solvates (including hydrates) and solvated salts of such racemates,enantiomers, diastereomers and tautomers and mixtures thereof.

Reference to the compounds of this invention as those of a specificformula or embodiment, e.g., Formula I (which includes the compounds ofFormulae II-VII) or any other generic structural formula or specificcompound described or claimed herein, is intended to encompass thespecific compound or compounds falling within the scope of the formulaor embodiment, including salts thereof, particularly pharmaceuticallyacceptable salts, solvates of such compounds and solvated salt formsthereof, where such forms are possible unless specified otherwise.

In the compounds of Formula I, the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of Formula I. Forexample, different isotopic forms of hydrogen (H) include protium (¹H)and deuterium (²H). Protium is the predominant hydrogen isotope found innature. Enriching for deuterium may afford certain therapeuticadvantages, such as increasing in vivo half-life or reducing dosagerequirements, or may provide a compound useful as a standard forcharacterization of biological samples. Isotopically-enriched compoundswithin Formula I can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the Schemes and Examplesherein using appropriate isotopically-enriched reagents and/orintermediates.

When the compounds of Formula I contain one or more acidic or basicgroups the invention also includes the corresponding physiologically ortoxicologically acceptable salts, in particular the pharmaceuticallyutilizable salts. Thus, the compounds of Formula I which contain acidicgroups can be used according to the invention, for example, as alkalimetal salts, alkaline earth metal salts or as ammonium salts. Examplesof such salts include but are not limited to sodium salts, potassiumsalts, calcium salts, magnesium salts or salts with ammonia or organicamines such as, for example, ethylamine, ethanolamine, triethanolamineor amino acids. Compounds of Formula I which contain one or more basicgroups, i.e. groups which can be protonated, can be used according tothe invention in the form of their acid addition salts with inorganic ororganic acids as, for example but not limited to, salts with hydrogenchloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid,benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid,naphthalenedisulfonic acids, oxalic acid, acetic acid, trifluoroaceticacid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formicacid, propionic acid, pivalic acid, diethylacetic acid, malonic acid,succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid,sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid,isonicotinic acid, citric acid, adipic acid, etc. If the compounds ofFormula I simultaneously contain acidic and basic groups in the moleculethe invention also includes, in addition to the salt forms mentioned,inner salts or betaines (zwitterions). Salts can be obtained from thecompounds of Formula I by customary methods which are known to theperson skilled in the art, for example by combination with an organic orinorganic acid or base in a solvent or dispersant, or by anion exchangeor cation exchange from other salts. The present invention also includesall salts of the compounds of Formula I which, owing to lowphysiological compatibility, are not directly suitable for use inpharmaceuticals but which can be used, for example, as intermediates forchemical reactions or for the preparation of pharmaceutically acceptablesalts.

Furthermore, compounds of the present invention may exist in amorphousform and/or one or more crystalline forms, and as such all amorphous andcrystalline forms and mixtures thereof of the compounds of Formula I areintended to be included within the scope of the present invention. Inaddition, some of the compounds of the instant invention may formsolvates with water (i.e., a hydrate) or common organic solvents. Suchsolvates and hydrates, particularly the pharmaceutically acceptablesolvates and hydrates, of the instant compounds are likewise encompassedwithin the scope of this invention, along with un-solvated and anhydrousforms.

Any pharmaceutically acceptable pro-drug modification of a compound ofthis invention which results in conversion in vivo to a compound withinthe scope of this invention is also within the scope of this invention.For example, esters can optionally be made by esterification of anavailable carboxylic acid group or by formation of an ester on anavailable hydroxy group in a compound. Similarly, labile amides can bemade. Pharmaceutically acceptable esters or amides of the compounds ofthis invention may be prepared to act as pro-drugs which can behydrolyzed back to an acid (or —COO— depending on the pH of the fluid ortissue where conversion takes place) or hydroxy form particularly invivo and as such are encompassed within the scope of this invention.Examples of pharmaceutically acceptable pro-drug modifications include,but are not limited to, —C₁₋₆ alkyl esters and —C₁₋₆ alkyl substitutedwith phenyl esters.

Accordingly, the compounds within the generic structural formulas,embodiments and specific compounds described and claimed hereinencompass salts, all possible stereoisomers and tautomers, physicalforms (e.g., amorphous and crystalline forms), solvate and hydrate formsthereof and any combination of these forms, as well as the saltsthereof, pro-drug forms thereof, and salts of pro-drug forms thereof,where such forms are possible unless specified otherwise.

Compounds of the present invention are effective at inhibiting thesynthesis of aldosterone by inhibiting CYP11B2 (aldosterone synthase)and, therefore, might be useful agents for the therapy and prophylaxisof disorders that are associated with elevated aldosterone levels.Accordingly, an object of the instant invention is to provide a methodfor inhibiting aldosterone synthase, and more particularly selectivelyinhibiting CYP11B2, in a mammal in need thereof, comprisingadministering a compound of Formula I to the mammal in an amounteffective to inhibit aldosterone synthesis, or more particularly toselectively inhibit CYP11B2, in the mammal. A selective inhibitor ofCYP11B2 is intended to mean a compound that preferentially inhibitsCYP11B2 as compared to CYP11B1. The inhibition of CYP11B2, as wellinhibition of CYP11B1, by the compounds of Formula I can be examined,for example, in the inhibition assays described below.

In general, compounds that have activity as aldosterone synthaseinhibitors can be identified as those compounds which have an IC₅₀ ofless than or equal to about 10 μM; preferably less than or equal toabout 250 nM; and most preferably less than or equal to about 100 nM, inthe V79-Human-CYP11B2 Assay described below. In general, aldosteronesynthase inhibitors that are selective for inhibition of CYP11B2 ascompared to CYP11B1 are those that show at least 3-fold greaterinhibition for CYP11B2 compared to CYP11B1; preferably at least 20-foldinhibition for CYP11B2 compared to CYP11B1; and more preferably at least100-fold greater inhibition for CYP11B2 compared to CYP11B1, in theV79-Human-CYP11B2 Assay as compared to the V79-Human-CYP11B1 Assay.

Due to their ability to inhibit CYP11B2, the compounds of the presentinvention may be useful to treat and/or ameliorate the risk forhypertension, hypokalemia, renal failure (e.g., chromic renal failure),restenosis, Syndrome X, nephropathy, post-myocardial infarction,coronary heart diseases, increased formation of collagen, fibrosis andremodeling following hypertension and endothelial dysfunction,cardiovascular diseases, renal dysfunction, liver diseases, vasculardiseases, cerebrovascular diseases, retinopathy, neuropathy,insulinopathy, endothelial dysfunction, heart failure (e.g., congestiveheart failure), diastolic heart failure, left ventricle diastolicdysfunction, diastolic heart failure, systolic dysfunction, ischemia,myocardial and vascular fibrosis, myocardial necrotic lesions, vasculardamage, myocardial infarction, left ventricular hypertrophy, cardiaclesions, vascular wall hypertrophy, endothelial thickening or necrosisof coronary arteries.

The dosage amount of the compound to be administered depends on theindividual case and is, as is customary, to be adapted to the individualcircumstances to achieve an optimum effect. Thus, it depends on thenature and the severity of the disorder to be treated, and also on thesex, age, weight and individual responsiveness of the human or animal tobe treated, on the efficacy and duration of action of the compoundsused, on whether the therapy is acute or chronic or prophylactic, or onwhether other active compounds are administered in addition to compoundsof Formula I. A consideration of these factors is well within thepurview of the ordinarily skilled clinician for the purpose ofdetermining the therapeutically effective or prophylactically effectivedosage amount needed to prevent, counter, or arrest the progress of thecondition. It is expected that the compound will be administeredchronically on a daily basis for a length of time appropriate to treator prevent the medical condition relevant to the patient, including acourse of therapy lasting days, months, years or the life of thepatient.

In general, a daily dose of approximately 0.001 to 30 mg/kg, preferably0.001 to 20 mg/kg, in particular 0.01 to 10 mg/kg (in each case mg perkg of bodyweight) is appropriate for administration to an adult weighingapproximately 75 kg in order to obtain the desired results. The dailydose is preferably administered in a single dose or, in particular whenlarger amounts are administered, can be divided into several, forexample two, three or four individual doses, and may be, for example butnot limited to, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg,2 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 75 mg, 100 mg, etc., ona daily basis. In some cases, depending on the individual response, itmay be necessary to deviate upwards or downwards from the given dailydose.

The term “patient” includes animals, preferably mammals and especiallyhumans, who use the instant active agents for the prevention ortreatment of a medical condition. Administering of the drug to thepatient includes both self-administration and administration to thepatient by another person. The patient may be in need of treatment foran existing disease or medical condition, or may desire prophylactictreatment to prevent or reduce the risk of said disease or medicalcondition.

The term “therapeutically effective amount” is intended to mean thatamount of a drug or pharmaceutical agent that will elicit the biologicalor medical response of a tissue, a system, animal or human that is beingsought by a researcher, veterinarian, medical doctor or other clinician.A “prophylactically effective amount” is intended to mean that amount ofa pharmaceutical drug that will prevent or reduce the risk of occurrenceof the biological or medical event that is sought to be prevented in atissue, a system, animal or human by a researcher, veterinarian, medicaldoctor or other clinician. The term “preventing” or “prevention” as usedherein refers to administering a compound before the onset of clinicalsymptoms.

It is understood that a specific daily dosage amount can simultaneouslybe both a therapeutically effective amount, e.g., for treatment ofhypertension, and a prophylactically effective amount, e.g., forprevention of myocardial infarction.

In the methods of treatment of this invention, the compound may beadministered via any suitable route of administration such as, forexample, orally, parenterally, or rectally in dosage unit formulationscontaining conventional non-toxic pharmaceutically acceptable carriers,adjuvants and vehicles. The term parenteral as used herein includessubcutaneous injections, intravenous, intramuscular, intrasternalinjection or infusion techniques. Oral formulations are preferred,particularly solid oral dosage units such as pills, tablets or capsules.

Accordingly, this invention also provides pharmaceutical compositionscomprised of a compound of Formula I and a pharmaceutically acceptablecarrier. For oral use, the pharmaceutical compositions of this inventioncontaining the active ingredient may be in forms such as pills, tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients, which are suitable for the manufacture oftablets. These excipients may be for example, inert diluents, such ascalcium carbonate, sodium carbonate, lactose, mannitol, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. Pharmaceutical compositionsmay also contain other customary additives, for example, wetting agents,stabilizers, emulsifiers, dispersants, preservatives, sweeteners,colorants, flavorings, aromatizers, thickeners, diluents, buffersubstances, solvents, solubilizers, agents for achieving a depot effect,salts for altering the osmotic pressure, coating agents or antioxidants.

Oral immediate-release and time-controlled release dosage forms may beemployed, as well as enterically coated oral dosage forms. Tablets maybe uncoated or they may be coated by known techniques for aestheticpurposes, to mask taste or for other reasons. Coatings can also be usedto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredients is mixed with water ormiscible solvents such as propylene glycol, PEGs and ethanol, or an oilmedium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Oilysuspensions may be formulated by suspending the active ingredient in avegetable oil, for example arachis oil, olive oil, sesame oil or coconutoil, or in mineral oil such as liquid paraffin. The oily suspensions maycontain a thickening agent, for example beeswax, hard paraffin or cetylalcohol. Sweetening agents and flavoring agents may be added to providea palatable oral preparation. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid. Syrups and elixirsmay be formulated with sweetening agents, for example glycerol,propylene glycol, sorbitol or sucrose.

The instant invention also encompasses a process for preparing apharmaceutical composition comprising combining a compound of Formula Iwith a pharmaceutically acceptable carrier. Also encompassed is thepharmaceutical composition which is made by combining a compound ofFormula I with a pharmaceutically acceptable carrier. The carrier iscomprised of one or more pharmaceutically acceptable excipients.Furthermore, a therapeutically effective amount of a compound of thisinvention can be used for the preparation of a medicament useful forinhibiting aldosterone synthase, inhibiting CYP11B2, for normalizing adisturbed aldosterone balance, or for treating or preventing any of themedical conditions described herein, in dosage amounts described herein.

The amount of active compound of Formula I and its pharmaceuticallyacceptable salts in the pharmaceutical composition may be, for examplebut not limited to, from 0.1 to 200 mg, preferably from 0.1 to 50 mg,per dose on a free acid/free base weight basis, but depending on thetype of the pharmaceutical composition and potency of the activeingredient it could also be lower or higher. Pharmaceutical compositionsusually comprise 0.5 to 90 percent by weight of the active compound on afree acid/free base weight basis.

Since the compounds of Formula I inhibit aldosterone synthase, apartfrom use as pharmaceutically active compounds in human medicine andveterinary medicine, they can also be employed as a scientific tool oras aid for biochemical investigations in which such an effect onaldosterone synthase and aldosterone levels is intended, and also fordiagnostic purposes, for example in the in vitro diagnosis of cellsamples or tissue samples. The compounds of Formula I can also beemployed as intermediates for the preparation of other pharmaceuticallyactive compounds.

One or more additional pharmacologically active agents (or therapeuticagents) may be administered in combination with a compound of Formula I.An additional active agent (or agents) is intended to mean apharmaceutically active agent (or agents) different from the compound ofFormula I. Generally, any suitable additional active agent or agents,including but not limited to anti-hypertensive agents,anti-atherosclerotic agents such as a lipid modifying compound,anti-diabetic agents and/or anti-obesity agents may be used in anycombination with the compound of Formula I in a single dosageformulation (a fixed dose drug combination), or may be administered tothe patient in one or more separate dosage formulations which allows forconcurrent or sequential administration of the active agents(co-administration of the separate active agents). Examples ofadditional active agents which may be employed include but are notlimited to the following pharmaceutically acceptable salts, metabolites,solvates, prodrugs, or polymorphs thereof: angiotensin converting enzyme(ACE) inhibitors (e.g, alacepril, benazepril, captopril, ceronapril,cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril,lisinopril, moexepril, moveltipril, perindopril, quinapril, ramipril,spirapril, temocapril, or trandolapril); dual inhibitors of angiotensinconverting enzyme (ACE) and neutral endopeptidase (NEP) such asomapatrilat, sampatrilat and fasidotril; angiotensin II receptorantagonists (e.g., candesartan, eprosartan, irbesartan, losartan,olmesartan, telmisartan, valsartan) neutral endopeptidase inhibitors(e.g., thiorphan and phosphoramidon), aldosterone antagonists, renininhibitors (e.g. enalkrein, RO 42-5892, A 65317, CP 80794, ES 1005, ES8891, SQ 34017, aliskiren(2(S),4(S),5(S),7(S)—N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamidhemifumarate) SPP600, SPP630 and SPP635), endothelin receptorantagonists, vasodilators, calcium channel blockers (e.g., amlodipine,bepridil, diltiazem, felodipine, gallopamil, nicardipine, nifedipine,niludipine, nimodipine, nisoldipine veraparmil), potassium channelactivators (e.g., nicorandil, pinacidil, cromakalim, minoxidil,aprilkalim, loprazolam), diuretics (e.g., hydrochlorothiazide);including loop diuretics such as ethacrynic acid, furosemide, bumetanideand torsemide, sympatholitics, beta-adrenergic blocking drugs (e.g.,acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, metoprolol,metoprolol tartate, nadolol, propranolol, sotalol, timolol); alphaadrenergic blocking drugs (e.g., doxazocin, prazocin or alphamethyldopa) central alpha adrenergic agonists, peripheral vasodilators(e.g. hydralazine), lipid lowering agents (e.g., simvastatin andlovastatin which are marketed as ZOCOR® and MEVACOR® in lactone pro-drugform and function as inhibitors after administration, andpharmaceutically acceptable salts of dihydroxy open ring acid HMG-CoAreductase inhibitors such as atorvastatin (particularly the calcium saltsold in LIPITOR®), rosuvastatin (particularly the calcium salt sold inCRESTOR®), pravastatin (particularly the sodium salt sold inPRAVACHOL®), and fluvastatin (particularly the sodium salt sold inLESCOL®); a cholesterol absorption inhibitor such as ezetimibe (ZETIA®),and ezetimibe in combination with any other lipid lowering agents suchas the HMG-CoA reductase inhibitors noted above and particularly withsimvastatin (VYTORIN®) or with atorvastatin calcium; niacin inimmediate-release or controlled release forms, and particularly inniacin in combination with a DP antagonist such as laropiprant(TREDAPTIVE) and/or with an HMG-CoA reductase inhibitor; niacin receptoragonists such as acipimox and acifran, as well as niacin receptorpartial agonists; metabolic altering agents including insulinsensitizing agents and related compounds (e.g., muraglitazar, glipizide,metformin, rosiglitazone), dipeptidyl peptidase 4 inhibitors (e.g.,sitagliptin, alogliptin, vildagliptin, saxagliptin, linagliptin,dutogliptin, and gemigliptin); or with other drugs beneficial for theprevention or the treatment of the above-mentioned diseases includingnitroprusside and diazoxide.

In general, the compounds in the invention may be produced by a varietyof processes know to those skilled in the art and by know processesanalogous thereto. The invention disclosed herein is exemplified by thefollowing preparations and examples which should not be construed tolimit the scope of the disclosure. Alternative mechanistic pathways andanalogous structures will be apparent to those skilled in the art. Thepractitioner is not limited to these methods and one skilled in the artwould have resources such as Chemical Abstracts or Beilstein at his orher disposal to assist in devising an alternative method of preparing aspecific compound.

The compounds of the present invention can be prepared according to theprocedures of the following Schemes using appropriate materials and arefurther exemplified by the specific Examples which follow. Moreover, byutilizing the procedures described herein, one of ordinary skill in theart can readily prepare additional compounds of the present inventionclaimed herein.

Throughout the synthetic schemes, abbreviations are used with thefollowing meanings unless otherwise indicated:

AcCN=acetonitrile; aq=aqueous, Ar=aryl; BSA=bovine serum albumin;Bu=butyl, t-Bu=tert-butyl; n-BuLi=n-butyllithium; conc,conc.=concentrated; DMAP=4-dimethylaminopyridine; DME=dimethyl ether;DCM=dichloromethane; DMEM=Dulbecco's modified eagle medium;DMF=N,N-dimethylformamide; eq.=equivalent(s);EDTA=ethylenediaminetetraacetic acid; Et=ethyl; EtOAc=ethyl acetate;EtOH=ethanol; FBS=Fetal Bovine Serum; h, hr=hour; HPLC=High pressureliquid chromatography; HTRF=homogenous time resolved fluorescence;i-PrOH=isopropanol; i-Pr=isopropyl; LCMS=liquid chromatography-massspectroscopy; Me=methyl; MeOH=methanol; min, min.=minute; MS=massspectroscopy; NCS=N-Chlorosuccinimide; NMR=nuclear magnetic resonance;PBS=phosphate buffered saline; Pd/C=palladium on activated carbon;Ph=phenyl; Pr=propyl; Py=pyridyl; OAc=acetate; RT, rt=room temperature;sat.=saturated; TEA=triethylamine; TFA=trifluroracetic acid;THF=tetrahydrofuran.

As will be known to those skilled in the art, in all schemes, theproducts of Formula I and all synthetic intermediates may be purifiedfrom unwanted side products, reagents and solvents by recrystallization,trituration, preparative thin layer chromatography, flash chromatographyon silica gel as described by W. C. Still et al, J. Org. Chem. 1978, 43,2923, or reverse-phase HPLC. Compounds purified by HPLC may be isolatedas the corresponding salt.

Additionally, in some instances the final compounds of Formula I andsynthetic intermediates may be comprised of a mixture of cis and transisomers, enantiomers or diastereomers. As will be known to those skilledin the art, such cis and trans isomers, enantiomers and diastereomersmay be separated by various methods including crystallization,chromatography using a homochiral stationary phase and, in the case ofcis/trans isomers and diastereomers, normal-phase and reverse-phasechromatography.

Chemical reactions were monitored by LCMS, and the purity and identityof the reaction products were assayed by LCMS (electrospray ionization)and NMR. Data for ¹H NMR are reported with chemical shift (δ ppm),multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet,br s=broad singlet, br m=broad multiplet), coupling constant (Hz), andintegration. Unless otherwise noted, all LCMS ions listed are [M+H]. Alltemperatures are degrees Celsius unless otherwise noted.

The following examples are provided so that the invention might be morefully understood. They should neither be construed as forming the onlygenus that is considered as the invention nor limiting the invention inany way.

Example 1

Step A tert-butyl 5 bromoindoline-1-carboxylate

BOC₂O (9.70 g, 44.4 mmol) was added to solution of commerciallyavailable 5-bromoindoline (8 g, 40.4 mmol) in THF (20 mL) and themixture was stirred at room temperature overnight. The solvent wasevaporated and the crude was chromatographed on a Biotage 65i columneluting with hexane/ethyl acetate (0-100%, 1.7 L) to give the titlecompound. ¹H NMR (500 MHz, CHCl₃-d): δ 7.74 (s, 1H), 7.28 (m 2H), 3.99(m, 2H), 3.10 (m, 2H), 1.59 (s, 9H), MS (M+1) 299.

Step B tert-butyl 5-(5-fluoropyridine-3-yl)indolin-1-carboxylate

To a stirred solution of 5 bromoindoline-1-carboxylate (1.0 g, 3.35mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(0.89 g, 4.0 mmol), in DME/H₂O (3:1, 12 mL) was added Pd(PPh₃)₄ (0.194g, 0.17 mol), and Na₂CO₃ (1.60 g, 15.1 mmol). The mixture was degassed,flushed with nitrogen and stirred at 80° C. for 2 h. The mixture wascooled to room temperature and diluted with ethyl acetate (30 mL). Theorganic layer was washed with water (30 mL), brine (30 ml), dried(Na₂SO₄), filtered and the solvent was evaporated. The residue waschromatographed on a biotage 45M column eluting with hexane/ethylacetate (0-100%, 1.2 L) to give the title compound. ¹H NMR (500 MHz,CHCl₃-d): δ 8.66 (m, 1H), 8.42 (m, 1H), 7.96 (m, 1H), 7.55-7.45 (m, 1H),7.43-7.36 (m, 2H), 4.06 (m, 2H), 3.19 (m, 2H), 1.65 (s, 9H), MS (M+1)315.

Step C 5-(5-fluoropyridin-3-yl)indoline

TFA (5 mL) was added to a solution of tert-butyl5-(5-fluoropridine-3-yl)indolin-1-carboxylate (1-3, 860 g, 2.74 mmol) inmethylene chloride (5 mL) at 0° C. and the mixture was stirred at roomtemperature overnight. The reaction mixture was diluted with methylenechloride (50 mL) and washed with saturated NaHCO₃ (30 mL), water (30 mL)and brine (30 mL), dried over Na₂SO₄, filtered and evaporated. The crudeproduct was chromatographed on a Biotage 45M column eluting withhexane/ethyl acetate (0-100%, 1.4 L) to give the title compound. ¹H NMR(500 MHz, CHCl₃-d): δ 8.64 (s, 1H), 8.37 (d, 1H), 7.54 (dt, 1H), 7.37(s, 1H), 7.26 (m, 1H), 6.74 (d, 1H), 3.67 (t, 2H), 3.14 (t, 2H), MS(M+1) 215.

Step D 1-(5-(5-fluoropyridin-3-yl)indolin-1-yl)ethanone

To a solution of 5-(5-fluoropyridin-3-yl)indoline (1-4 0.040 g, 0.187mmol) in methylene chloride (5 mL), TEA (0.078 mL, 0.56 mmol) and acetylchloride (0.030 g, 0.373 mmol) were added to the reaction mixture. Thereaction mixture was stirred at room temperature for 1 h. The solventwas evaporated and the crude was purified by reverse phase Gilson(SunFire™ C18 column, eluting with water/AcCN 5-40% in 12 min.) to givethe title compound. ¹H NMR (500 MHz, CDCl₃): δ 8.67 (s, 1H); 8.44 (s,1H); 8.33 (d, J=8.3 Hz, 1H); 7.61 (d, J=9.5 Hz, 1H); 7.46-7.41 (m, 2H);4.24-4.11 (m, 2H); 3.39-3.27 (m, 2H); 2.49 (s, 1H); 2.29 (s, 3H), MS(M+1) 257.

The compounds in Table 1 were all prepared using the chemistry describedin Example 1, step B.

TABLE 1 MS H¹ NMR Ex Structure IUPAC Name (M + 1) 500 MHz, CDCl₃  2

1-(7-chloro-5-(5- fluoropyridine- 3-yl)indolin-1- yl)ethanone 291.17 δ9.78 (s, 1 H); 9.62 (s, 1 H); 8.74 (d, J = 9.3 Hz, 1 H); 8.58 (s, 1 H);8.51 (s, 1 H); 5.41-5.35 (m, 2 H); 4.29 (t, J = 7.6 Hz, 2 H); 3.48 (s, 3H)  3

1-(7-chloro-5-(5- methoxypyridin-3- yl)indolin-1- yl)ethanone 303.13 δ9.70 (s, 1 H); 9.52 (s, 1 H); 8.85 (s, 1 H); 8.57 (s, 1 H); 8.51 (s, 1H); 5.38-5.33 (m, 2 H); 5.15 (s, 3 H); 4.31-4.25 (m, 2 H); 3.46 (s, 3 H) 4

(S)-1-(7-chloro-5-(5- (1,1,1,-trifluoro-2- hydroxypropan-2-yl)pyridine-3- yl)indolin-1- yl)ethanone 385.07 δ 8.89 (s, 1 H); 8.85(s, 1 H); 8.34 (s, 1 H); 7.42 (d, J = 13.6 Hz, 2 H); 5.72 (bs, 1 H);4.28-4.22 (m, 2 H); 3.20-3.14 (m, 2 H); 2.36 (d, J = 2.1 Hz, 3 H); 1.93(s, 3 H)  5

(R)-1-(7-chloro-5- (5-(1,1,1,-trifluoro- 2hydroxypropan-2-yl)pyridine-3- yl)indolin-1- yl)ethanone 385.07 δ 8.79 (d, J = 13.6 Hz,2 H); 8.18 (s, 1 H); 7.45 (s, 1 H); 7.40 (s, 1 H); 4.28-4.21 (m, 2 H);3.16 (t, J = 7.6 Hz, 2 H); 2.35 (s, 3 H); 1.91 (s, 3 H  6

1-(7-chloro-5-(5- (trifluoromethyl) pyridine-3-yl)indolin-1- yl)ethanone341 δ 9.00 (d, J = 2.1 Hz, 1 H); 8.90 (s, 1 H); 8.07 (s, 1 H); 7.49 (s,1 H); 7.47-7.39 (m, 1 H); 4.30-4.23 (m, 2 H); 3.18 (t, J = 7.6 Hz, 2 H);2.36 (s, 3 H)  7

1-(7-chloro-5-(4- (trifluoromethyl) pyridine-3-yl)indolin-1- yl)ethanone341 δ 9.89 (bs, 1 H); 9.67 (bs, 1 H); 8.36 (m, 1 H); 8.26 (m, 1 H); 8.16(m, 1 H); 5.35-5.30 (m, 2 H); 4.25-4.20 (m, 2 H); 3.43 (s, 9 H)  8

1-(7-chloro-5-(5- fluoro-4- methylpyridin-3- yl)indolin-1- yl)ethanone312.14 8.42 (s, 1 H); 8.29 (s, 1 H); 7.21 (s, 1 H); 7.12 (s, 1 H); 4.26(t, J = 7.5 Hz, 2 H); 3.15 (t, J = 7.6 Hz, 2 H); 2.37 (s, 3 H); 2.29 (d,J = 2.2 Hz, 3 H)  9

1-(7-chloro-5-(4- ethyl-5- fluoropyridin-3- yl)indolin-1- yl)ethanone319.11 δ 8.42 (s, 1 H); 8.27 (s, 1 H); 7.21 (s, 1 H); 7.11 (s, 1 H);4.27 (t, J = 7.6 Hz, 2 H); 3.16 (t, J = 7.6 Hz, 2 H); 2.70 (q, J = 7.6Hz, 2 H); 2.37 (s, 3 H); 1.17 (t, J = 7.5 Hz, 3 H) 10

5-(1-acetyl-7- chloroindolin-5-yl) 4- methylnicotinotrile 312.10 δ8.84-8.75 (m, 1 H); 8.63-8.58 (m, 1 H); 7.20 (s, 1 H); 7.10 (s, 1 H);4.27 (t, J = 7.6 Hz, 2H); 3.17 (t, J = 7.6 Hz, 2 H); 2.54 (s, 3 H); 2.37(s, 3 H) 11

1-(7-chloro-5- (isoquinolin-4-yl) indolin-1- yl)ethanone 323.09 9.30 (s,1 H); 8.49 (s, 1 H); 8.09 (d, J = 8.1 Hz, 1 H); 7.94 (d, J = 8.5 Hz, 1H); 7.78-7.67 (m, 2 H); 7.41 (s, 1 H); 7.35-7.24 (m, 1 H); 4.30 (t, J =7.5 Hz, 2 H); 3.18 (t, J = 7.5 Hz, 2 H) 12

1-(7-fluoro-5- (pyridine-3-yl) indolin-1-yl) ethanone 257.10 δ 9.08 (s,1 H); 8.75 (d, J = 5.2 Hz, 1 H); 8.34 (d, J = 8.0 Hz, 1 H); 7.83 (dd, J= 8.1, 5.2 Hz, 1 H); 7.36 (s, 1 H); 7.28 (m, 1H); 4.32- 4.24 (m, 2 H);3.23- 3.17 (m, 2 H); 2.35 (d, J = 4.2 Hz, 3 H) 13

(S)-1-(7-fluoro-5-(5- (1,1,1-trifluoro-2- hydroxypropan-2- yl)pyridin-3-yl)indolin-1- yl)ethanone 369.10 δ 9.07-8.99 (m, 1 H); 8.97 (s, 1 H);8.55 (s, 1 H); 7.36 (s, 1 H); 7.29 (m, 1H); 4.32-4.25 (m, 2H); 3.78 (bs,1H); 3.26-3.20 (m, 2 H); 2.37 (d, J = 3.9 Hz, 3 H); 1.99 (s, 3 H) 14

(R)-1-(7-fluoro-5-(5- (1,1,1-trifluoro-2- hydroxypropan-2-yl)pyridin-3-yl) indolin-1-1)ethanone 369.12 δ 9.03-8.94 (m, 1 H); 8.92 (s,1 H); 8.46 (m, 1 H); 7.35 (s, 1 H); 7.28 (m, 1H); 4.32-4.26 (m, 2 H);3.22 (m, 2 H); 2.36 (d, J = 3.9 Hz, 3 H); 1.98 (s, 3 H) 15

1-(7-fluoro-5-(4- methylpyridin-3- yl)indolin-1-yl) ethanone 272.128.71-8.61 (m, 2 H); 7.68 (d, J = 5.7 Hz, 1 H); 7.06-6.95 (m, 2 H);4.31-4.24 (m, 2 H); 3.21-3.14 (m, 2 H); 2.56 (s, 3 H); 2.35 (d, J = 4.0Hz, 3 H) 16

5-(1-acetyl-7- fluoroindolin-5- yl)nicotinonitrile 282.10 δ 9.02 (s, 1H); 8.89 (s, 1 H); 8.13-8.11 (m, 1 H); 7.29 (s, 1 H); 7.23 (m, 1H);4.31-4.24 (m, 2 H); 3.22-3.15 (m, 2 H); 2.35 (d, J = 4.4 Hz, 3H) 17

5-(1-acetyl-7- fluoroindolin-5-yl)- 4-methylnicotino nitrile 296.12 δ8.92-8.76 (m, 1 H); 8.62 (s, 1 H); 7.03-6.91 (m, 2 H); 4.31-4.24 (m, 2H); 3.20-3.13 (m, 2 H); 2.55 (s, 3 H); 2.36 (d, J = 4.2 Hz, 3 H) 18

1-(7-fluoro-5-(5- fluoropyridine-3- yl)indolin-1-yl)- ethanone 275.10 δ8.68 (s, 1 H); 8.50 (s, 1 H); 7.65-7.61 (m, 1 H); 7.30 (d, J = 2.6 Hz, 1H); 7.24 (m, 1H); 4.31-4.24 (m, 2 H); 3.21-3.14 (m, 2 H); 2.35 (d, J =4.4 Hz, 3 H) 19

1-(7-fluoro-5-(5- fluoro-4- methylpyridine-3- yl)indolin-1-yl)- ethanone289.11 δ 8.50 (s, 1 H); 8.41 (s, 1 H); 7.06-6.95 (m, 2 H); 4.32-4.25 (m,2 H); 3.21-3.14 (m, 2 H); 2.40-2.35 (m, 6 H) 20

1-(5-(4-ethyl-5- fluoropyridine-3-yl)- 7-fluoroindolin-1- yl)ethanone303.13 δ 8.51 (s, 1 H); 8.38 (s, 1 H); 7.04-6.93 (m, 2 H); 4.33-4.25 (m,2 H); 3.21-3.14 (m, 2 H); 2.79 (dd, J = 15.0, 7.5 Hz, 2H); 2.37 (d, J =4.1 Hz, 3 H); 1.25-1.17 (m, 3 H) 21

1-propanoyl-5- pyridin-3-yl-2,3- dihydro-1H-indole 253.13 δ 1.26 (t, J =7.3 Hz, 3H), 2.48 (q, J = 7.3 Hz, 2H), 3.28 (t, J = 8.3 Hz, 2H), 4.11(t, J = 8.3 Hz, 2H), 7.33 (dd, J = 4.9, 7.8 Hz, 1H), 7.41 (d, J = 3.4Hz, 1H), 7.42 (s, 1H), 7.84 (dt, J = 2.0, 7.8 Hz, 1H), 8.34 (d, J = 8.0Hz, 1H), 8.55 (d, J = 4.0 Hz, 1H), 8.82 (d, J = 2.2 Hz, 1H) 22

1-(3-chloro- propanoyl)-5- pyridin-3-yl-2,3- dihydro-1H-indole 287.35 δ2.95 (t, J = 6.8 Hz, 2H), 3.30 (t, J = 8.5 Hz, 2H), 3.93 (t, J = 6.8 Hz,2H), 4.15 (t, J = 8.5 Hz, 2H), 7.34 (dd, J = 4.8, 7.8 Hz, 1H), 7.44 (m,2H), 7.84 (dt, J = 1.9, 7.8 Hz, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.56 (d,J = 4.5 Hz, 1H), 8.82 (d, J = 1.9 Hz, 1H). 23

1-(cyclopropyl- carbonyl)-5-pyridin- 3-yl-2,3-dihydro- 1H-indole 265.66δ 0.91 (m, 2H), 1.15 (m, 2H), 1.78 (s, br, 1H), 3.30 (t, J = 8.3 Hz,2H), 4.33 (t, J = 8.3 Hz, 2H), 7.34 (dd, J = 4.8, 7.8 Hz, 1H), 7.40 (m,2H), 7.85 (dt, J = 2.0, 7.8 Hz, 1H), 8.26 (s, br, 1H), 8.55 (d, J = 4.6Hz, 1H), 8.82 (d, J = 1.8 Hz, 1H). 24

1-[(4-fluorophenyl) carbonyl]-5-pyridin- 3-yl-2,3-dihydro- 1H-indole319.23 δ 3.16 (t, J = 8.3 Hz, 2H), 4.07 (t, J = 8.3 Hz, 2H), 7.34 (m,2H), 7.46 (dd, J = 4.8, 8.0 Hz, 1H), 7.56 (s, br, 1H), 7.67 (d, J = 0.9Hz, 1H), 7.70 (m, 2H), 8.05 (d, J = 8.0 Hz, 1H), 8.53 (dd, J = 1.5, 4.7Hz, 1H), 8.87 (d, J = 1.8 Hz, 1H). 25

1-[(4-methoxy- phenyl)carbonyl]-5- pyridin-3-yl-2,3- dihydro-1H-indole331.36 δ 3.16 (t, J = 8.3 Hz, 2H), 3.83 (s, 3H), 4.11 (t, J = 8.3 Hz,2H), 7.04 (m, 2H), 7.45 (dd, J = 4.8, 7.9 Hz, 1H), 7.54 (d, J = 7.7 Hz,1H), 7.60 (m, 2H), 7.66 (s, 1H), 8.04 (dt, J = 2.0, 8.0 Hz, 1H), 8.52(dd, J = 1.5, 4.7 Hz, 1H), 8.87 (d, J = 2.0 Hz, 1H). 26

1-(Phenylacetyl)-5- pyridin-3-yl-2,3- dihydro-1H-indole 315.66 δ 3.24(t, J = 8.5 Hz, 2H), 3.84 (s, 2H), 4.13 (t, J = 8.5 Hz, 2H), 7.28 (m,1H), 7.34 (m, 5H), 7.39 (s, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.83 (dt, J =1.8, 7.9 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.55 (d, J = 1.3, 4.7 Hz,1H), 8.81 (d, J = 2.1 Hz, 1H). 27

5-Pyridin-3-yl-1- (thiophen-2- ylcarbonyl)-2,3- dihydro-1H-indole 307.57δ 3.30 (t, J = 8.3 Hz, 2H), 4.45 (t, J = 8.3 Hz, 2H), 7.13 (t, J = 8.3Hz, 1H), 7.34 (dd, J = 4.8, 7.9 Hz, 1H), 7.44 (m, 2H), 7.56 (dd, J =0.9, 5.0 Hz, 1H), 7.62 (dd, J = 0.8, 3.7 Hz, 1H), 7.83 (dt, J = 2.0, 7.9Hz, 1H), 8.18 (s, br, 1H), 8.56 (dd, J = 1.5, 4.8 Hz, 1H), 8.83 (d, J =2.0 Hz, 1H). 28

4-(1-acetyl-2,3- dihydro-1H-indol-5- yl)isoquinoline 289.46 δ 2.28 (s,3H), 3.30 (t, J = 8.4 Hz, 2H), 4.16 (t, J = 8.4 Hz, 2H), 7.32 (s, 1H),7.35 (d, J = 8.2 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.67 (t, J = 7.4 Hz,1H), 7.93 (d, ³J = 8.4 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 8.35 (d, J =8.2 Hz, 1H), 8.46 (s, 1H), 9.24 (s, 1H). 29

4-(1-propanoyl-2,3- dihydro-1H-indol-5- yl)isoquinoline 303.57 δ 1.28(t, J = 7.3 Hz, 3H), 2.51 (q, J = 7.3 Hz, 2H), 3.30 (t, J = 8.4 Hz, 2H),4.14 (t, J = 8.4 Hz, 2H), 7.32 (s, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.62(t, J = 7.3 Hz, 1H), 7.67 (t, J = 7.3 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H),8.03 (d, J = 8.0 Hz, 1H), 8.39 (t, J = 8.1 Hz, 1H), 8.46 (s, 1H), 9.23(s, 1H). 30

4-[1-(2-methyl- propanoyl)-2,3- dihydro-1H-indol-5- yl]isoquinoline315.36 δ 1.28 (d, J = 6.7 Hz, 6H), 2.84 (m, 1H), 3.31 (t, J = 7.9 Hz,2H), 4.24 (t, J = 8.5 Hz, 2H), 7.35 (m, 2H), 7.66 (m, 1H), 7.72 (m, 1H),7.97 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 8.42 (s, J = 7.8 Hz,1H), 8.47 (s, 1H), 9.26 (s, 1H). 31

4-[1-(cyclopropyl- carbonyl)-2,3- dihydro-1H-indol-5- yl]isoquinoline315.36 δ 0.93 (m, 2H), 1.17 (m, 2H), 1.81 (s, br, 1H), 3.33 (s, br, 2H),4.37 (s, br, 2H), 7.34 (m, 2H), 7.62-7.70 (m, 2H), 7.94 (d, J = 8.1 Hz,1H), 8.04 (d, J = 7.7 Hz, 1H), 8.32 (s, br, 1H), 8.47 (s, 1H), 9.24 (s,1H). 32

1-(7-chloro-5-(5- fluoropyridin-3- yl)indolin-1-yl)- 2,2,2-trifluoroethanone 385.59 δ 3.41 (t, J = 7.6 Hz, 2H), 4.41 (t, J = 7.6Hz, 2H), 7.70-7.71 (m, 1H), 7.76- 7.77 (m, 1H), 7.94- 7.97 (m, 1H),8.51- 8.52 (d, J = 2.8 Hz, 1H), 8.79 (t, J = 1.6 Hz, 1H) 33

2,2,2-trifluoro-1-(7- fluoro-5-(5- fluoropyridin-3- yl)indolin-1-yl)ethanone 369.68 δ 3.42 (d, J = 7.7 Hz, 2H), 4.43 (td, J = 7.8 Hz, J =0.9 Hz, 2H), 7.62- 7.66 (m, 1H), 7.92-7.98 (m, 1H), 8.52 (d, J = 2.8 Hz,1H), 8.80 (t, J = 2.0 Hz, 1H). 34

1-(5-(pyridin-3- yl)indolin-1- yl)ethanethione 255.32 δ 2.75 (s, 3H),2.99 (s, 3H), 3.18 (t, J = 8.2 Hz, 2H), 4.42 (t, J = 8.2 Hz, 2H), 4.46(t, J = 8.2 Hz, 2H), 7.47-7.50 (m, 2H), 8.10-8.12 (m, 2H), 8.55-8.57 (m,2H), 9.52 (d, J = 8.2 Hz, 1H)

Example 35

TEA (0.078 mL, 0.56 mmol) and isocyanatomethane (0.021 g, 0.373 mmol)were added to a solution of 5-(5-fluoropyridin-3-yl)indoline (0.040 g,0.187 mmol) in methylene chloride (5 mL). The mixture was stirred atroom temperature for 1 h. The solvent was evaporated and the crude waspurified by reverse phase Gilson (SunFire™ C18 column, eluting withwater/AcCN 5-40% in 12 min.) to yield5-(5-fluoropyridin-3-yl)-N-methylindoline-1-carboxamide. ¹H NMR (500MHz, CDCl₃). δ 8.66 (s, 1H); 8.42 (s, 1H); 8.06 (d, J=8.4 Hz, 1H); 7.57(dt, J=9.8, 2.2 Hz, 1H); 7.46-7.38 (m, 2H); 4.65 (d, J=5.6 Hz, 1H); 3.99(t, J=8.7 Hz, 2H); 3.29 (t, J=8.7 Hz, 2H); 2.96 (d, J=4.6 Hz, 3H), MS(M+1) 272.

The compounds in Table 2 were all prepared using the chemistry describedin Example 35

TABLE 2 MS H¹ NMR Ex Structure IUPAC Name (M + 1) 500 MHz, CDCl₃ 36

N-ethyl-5-(5- fluoropyridin-3- yl)indoline-1- carboxamide 286 δ 8.67 (s,1 H); 8.42 (s, 1 H); 8.06 (d, J = 8.4 Hz, 1 H); 7.59 (d, J = 9.7 Hz, 1H); 7.44-7.36 (m, 2 H); 4.65 (s, 1 H); 3.99 (t, J = 8.7 Hz, 2 H);3.45-3.39 (m, 2 H); 3.31-3.24 (m, 2 H); 1.29-1.19 (m, 3 H) 37

N-(tert-butyl)5-(5- fluoropyridin-3- yl)indolin-1- carboxamide 313 δ8.67 (s, 1 H); 8.42 (s, 1 H); 8.01 (d, J = 8.4 Hz, 1 H); 7.61 (d, J =9.6 Hz, 1 H); 7.43-7.36 (m, 2 H); 4.49 (s, 1 H); 3.99-3.92 (m, 2 H);3.29-3.22 (m, 2 H); 1.46 1.46 (m, 9H) 38

5-(5-fluoropyridin- 3-yl)-N- phenylindoline-1- carboxamide 335.3 δ 8.68(s, 1 H); 8.44 (s, 1 H); 8.09 (d, J = 8.3 Hz, 1 H); 7.61 (d, J = 9.6 Hz,1 H); 7.56-7.40 (m, 5H); 7.40-7.23 (m, 2 H); 6.59 (s, 1 H); 4.19-4.11(m, 2 H); 3.37-3.29 (m, 2 H) 39

methyl 5-(5- fluoropyridin-3- yl)indoline-1- carboxylate 273.4 δ 8.68(s, 1 H); 8.45 (s, 1 H); 8.00 (s, 1 H); 7.60 (d, J = 9.6 Hz, 1 H);7.47-7.38 (m, 2 H); 4.11 (bs, 2 H); 3.89 (bs, 2H); 3.26-3.19 (m, 3H) 40

ethyl 5-(5- fluoropyridin-3- yl)indoline-1- carboxylate 287 δ 8.68 (s, 1H); 8.44 (s, 1H); 8.00 (s, 1 H); 7.61 (d, J = 9.6 Hz, 1 H); 7.47-7.39(m, 2 H); 4.34 (bs, 2 H); 4.15- 4.08 (m, 2 H); 3.26- 3.19 (m, 2 H); 1.40(m, 3H) 41

tert-butyl 5- (5fluoropyridin- 3-yl)indoline-1- carboxylate 315 δ 8.67(s, 1 H); 8.43 (s, 1 H); 7.97 (s, 1 H); 7.60 (d, J = 9.8 Hz, 1 H);7.44-7.37 (m, 2 H); 4.27-3.87 (m, 2 H); 3.23-3.15 (m, 2 H); 1.60 (s, 9H)42

phenyl 5-(5- fluoropyridin-3- yl)indoline-1- carboxylate 335.3 δ 8.69(s, 1 H); 8.46 (s, 1 H); 8.02 (d, J = 8.1 Hz, 1 H); 7.63 (d, J = 9.5 Hz,1 H); 7.48-7.42 (m, 5 H); 7.29-7.24 (m, 2H); 4.35 (m, 2 H); 3.33 (m, 2H)

Example 43

Step A 1-(5-bromo-7-chloroindolin-1-yl)ethanone

A mixture of commercially available 1-acetyl-5-bromoindoline (43-1, 7.0g, 29.2 mmol) and NCS (4.28 g, 32.1 mmol) in 300 mL of acetonitrile washeated under reflux for 24 h. The reaction mixture was cooled to roomtemperature and the solvent was removed under reduced pressure. Theresidue was chromatography on a Biotage 65i column eluting withhexane/ethyl acetate (0-5-%) to give the title compound. ¹H NMR (500MHz, CDCl₃): δ 7.45 (s, 0H); 7.29 (s, 1H); 4.19 (t, J=7.6 Hz, 2H);3.10-3.03 (m, 2H); 2.30 (s, 3H), MS (M+1) 275.5.

Step B: 1-(7-chloro-5-(pyridin-3-yl)indolin-1-yl)ethanone

The title compound was prepared according to the procedure of Example 1step B using 1-(5-bromo-7-chloroindolin-1-yl)ethanone in place ofbromoindoline-1-carboxylate as the starting material. The product waspurified by reverse phase Gilson (SunFire™ C18 column, eluting withwater/AcCN 5-50% in 12 min. to give the title compound. ¹H NMR (500 MHz,CDCl₃): δ 10.16 (s, 1H); 9.89 (s, 1H); 9.53 (s, 1H); 9.33 (d, J=7.8 Hz,1H); 8.85 (s, 1H); 8.64 (s, 1H); 5.45-5.38 (m, 2H); 4.37-4.31 (m, 2H);3.56-3.48 (m, 3H). MS (M+1) 273.

Example 44

Step A 6-chloroindoline

To a stirred solution of 6-chloro-1H-indole (5 g, 33.0 mmol) in glacialacetic acid (93 ml) at 15° C. under an atmosphere of nitrogen was addedin one portion sodium cyanoborohydride (6.22 g, 99 mmol). The mixturewas stirred at 15° C. for 2 h. Water (500 mL) was added and the mixturewas cooled in an ice bath and slowly made strongly basic with sodiumhydroxide pallets. The mixture was extracted with ether (4×200 mL). Theether extracts were washed with water (400 ml), brine (400 mL) driedover anhydrous potassium carbonate, and concentrated in vacuo to givethe title compound. ¹H NMR (500 MHz, CDCl₃): δ 7.02 (d, J=7.8 Hz, 1H);6.68 (dd, J=7.8, 1.9 Hz, 1H); 6.62 (d, J=1.9 Hz, 1H); 3.61 (t, J=8.4 Hz,2H); 3.54 (s, 1H); 3.01 (t, J=8.4 Hz, 2H), MS (M+1) 14.3.

Step B 1-(6-chloroindolin-1-yl)ethanone

To a stirred solution of 6-chloroindoline (44-1, 4.0 g, 26.0 mmol) at 0°C. in methylene chloride (25 mL) was added TEA (14.5 mL, 104 mmol) andacetyl chloride (4.1 g, 53 mmol). The mixture was stirred to roomtemperature (1 h) and diluted with methylene chloride (100 ml). Theorganic layer was washed with saturated aqueous NaHCO₃ (2×50 mL), water(50 mL), brine (50 ml) dried (MgSO₄), filtered and the solvent wasevaporated under reduced pressure to give the title compound. ¹H NMR(500 MHz, CDCl₃): δ 8.25 (s, 1H); 7.08 (d, J=7.9 Hz, 1H); 6.99 (d, J=8.0Hz, 1H); 4.13-4.05 (m, 2H); 3.21-3.07 (m, 2H); 2.23 (s, 3H), MS (M+1)180.17.

Step C 1-(5-bromo-6-chloroindolin-1-yl)ethanone

To a stirred solution of 1-(6-chloroindolin-1-yl)ethanone (44-2, 4.2 g,21.4 mmol) in acetic acid (200 mL) at 0° C. was added bromine (1.1 mL,21.4 mmol). The mixture was stirred to room temperature (4 h) and theproduct (ppt.) was filtered off to give the title compound. ¹H NMR (500MHz, CDCl₃): δ 8.31 (s, 1H); 7.35 (s, 1H); 4.08 (t, J=8.5 Hz, 2H);3.19-3.12 (m, 2H); 2.22 (s, 3H), MS (M+1) 275.2.

Step D 1-(6-chloro-5-(pyridin-3-yl)indoline-1-yl)ethanone

The title compound was prepared according to the procedure of Example 1step B using 1-(5-bromo-6-chloroindolin-1-yl)ethanone in place ofbromoindoline-1-carboxylate as the starting material. The product waspurified by reverse phase Gilson (SunFire™ C18 column, eluting withwater/AcCN 5-50% in 12 min. to give the title compound. ¹H NMR (500 MHz,CDCl₃): δ 8.92 (s, 1H); 8.81 (d, J=5.6 Hz, 1H); 8.45 (s, 1H); 8.06 (bs,1H); 7.89 (t, J=6.8 Hz, 1H); 7.21 (s, 1H); 4.24-4.16 (m, 2H); 3.32-3.25(m, 2H); 2.31 (s, 3H), MS (M+1) 273.03

The compounds in Table 3 were prepared using the chemistry described inExample 44.

TABLE 3 MS H¹ NMR Ex Structure IUPAC Name (M + 1) 500 MHz, CDCl₃ 45

1-(6-chloro-5-(5- fluoropyridine-3- yl)indolin-1- yl)ethanone 291.07 δ8.55 (m, 2 H); 8.43 (s, 1 H); 7.77 (d, J = 8.8 Hz, 1 H); 7.17 (s, 1 H);4.22-4.14 (m, 2 H); 3.30-3.23 (m, 2 H); 2.30 (s, 3 H) 46

1-(6-chloro-5-(4- ethyl-5- fluoropyridine-3- yl)indolin-1- yl)ethanone319.10 δ 8.55 (s, 1 H); 8.31 (s, 1 H); 7.68 (m, 1 H); 7.51 (m, 1 H);4.23- 4.07 (m, 2 H); 3.30- 3.23 (m, 2 H); 2.78- 2.68 (m, 1 H); 2.61-2.51 (m, 1 H); 2.30 (s, 3H); 1.09 (t, J = 7.4 Hz, 3 H) 47

1-(6-fluoro-5- (pyridin-3- yl)indolin-1- yl)ethanone 257.11 δ 8.93 (s, 1H); 8.68 (s, 1 H); 8.26 (s, 1 H); 8.13 (d, J =12.4 Hz, 1 H); 7.69 (m, 1H); 7.28 (m, 1H); 4.20 (t, J = 8.4 Hz, 2 H); 3.31- 3.24 (m, 2 H); 2.29(s, 2H) 48

1-(6-fluoro-5-(5- fluoropyridin-3- yl)indolin-1- yl)ethanone 275.10 δ8.66 (s, 1 H); 8.50 (s, 1 H); 8.12 (d, J = 12.4 Hz, 1 H); 7.80 (d, J =9.2 Hz, 1 H); 7.27 (m, 1H); 4.19 (t, J = 8.4 Hz, 2 H); 3.31-3.24 (m, 2H); 2.29 (s, 3 H) 49

1-(5-(4-ethyl-5- fluoropyridin-3-yl)- 6-fluoroindolin-1- yl)ethanone303.13 δ 8.54 (s, 1 H); 8.39 (s, 1 H); 8.13 (d, J = 11.1 Hz, 1 H); 7.04(d, J = 7.0 Hz, 1 H); 4.21 (t, J = 8.4 Hz, 2 H); 3.31- 3.24 (m, 2 H);2.72 (d, J = 8.6 Hz, 2 H); 2.31 (s, 3 H); 1.16-1.07 (m, 3 H)

Example 50

Step A 5-(pyridin-3-yl)-1H-indole

A suspension of 5-bromoindole (250 mg, 1.26 mmol), pyridin-3-ylboronicacid (186 mg, 1.51 mmol), sodium carbonate (667 mg, 6.30 mmol) andtetrakis(triphenylphosphine)palladium (O) (73 mg, 0.06 mmol) indimethoxyethane (30 mL) and water (10 mL) was stirred at 90° C. undernitrogen for 2 h. The reaction mixture was cooled to room temperatureslowly and then diluted with water. The aqueous layer was extracted withEtOAc and the combined organic layers were washed with brine twice anddried over MgSO₄. After evaporation in vacuo, the resulting residue waspurified by flash chromatography on silica gel (EtOAc/n-hexane, 1:100 to1:2) to yield a pale yellow solid. ¹H-NMR (500 MHz, CDCl₃): δ 7.37 (ddd,J=0.8, 4.8, 7.9 Hz, 1H), 7.41 (m, 1H), 7.49 (m, 2H), 7.59 (m, 2H), 7.88(dt, J=2.0, 7.9 Hz, 1H), 8.60 (dd, J=1.6, 4.8 Hz, 1H), 8.86 (dd, J=0.6,2.4 Hz, 1H).

Step B 1-Acetyl-5-pyridin-3-yl-1H-indole

To a stirred solution of 50-1 (163 mg, 0.84 mmo) in 1,2-dichloroethane(6 mL) was added triethylamine (0.17 ml, 1.26 mmol), acetic anhydride(0.30 ml, 3.28 mmol) and DMAP (20 mg, 0.16 mmol) in sequence under N₂.The solution was heated to 60° C. for 8 h. Upon cooling to ambienttemperature, the reaction was diluted with EtOAc (6 mL) and washed witha saturated solution of ammonium chloride, and the aqueous layer wasextracted with EtOAc (3×10 mL).The combined organic layers were driedover MgSO₄ and concentrated in vacuo. The crude product was purified byflash column chromatography on silica gel (EtOAc/n-hexane, 1:50 to 1:2)to give pale yellow crystals. mp 138-140° C., R_(f)=0.16(EtOAc/n-hexane, 1:1). ¹H-NMR (500 MHz, CDCl₃): δ 2.67 (s, 3H), 6.71 (d,J=3.8 Hz, 1H), 7.38 (dd, J=4.8, 7.9 Hz, 1H), 7.48 (d, J=3.7 Hz, 1H),7.57 (dd, J=1.8, 8.5 Hz, 1H), 7.77 (d, J=1.7 Hz, 1H), 7.93 (dt, J=1.8,7.9 Hz, 1H), 8.54 (d, J=8.5 Hz, 1H), 8.59 (dd, J=1.5, 4.8 Hz, 1H), 8.90(d, J=1.8 Hz, 1H). ¹³C-NMR (125 MHz, CDCl₃): δ 23.9, 109.2, 117.1,119.4, 123.6, 124.4, 126.1, 131.1, 133.4, 134.7, 135.4, 137.0, 148.0,148.3, 168.5. MS (ESI) m/z=237.36 [M+H]⁺.

The compounds in Table 4 were prepared using the chemistry described inExample 50.

TABLE 4 MS H¹ NMR Ex Structure IUPAC Name (M + 1) 500 MHz, CDCl₃ 51

4-(1-acetyl-1H- indol-5-yl) isoquinoline 287.57 δ 2.70 (s, 3H), 6.73 (d,J = 3.7 Hz, 1H), 7.51 (dd, J = 1.7, 8.5 Hz, 1H), 7.53 (d, J = 3.7 Hz,1H), 7.66 (m, 2H), 7.70 (d, J = 1.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H),8.06 (dd, J = 1.3, 7.4 Hz, 1H), 8.54 (s, 1H), 8.59 (d, J = 8.4 Hz, 1H),9.28 (s, 1H)

Example 52

Step A 1-Acetyl-5-bromo-2,3-dihydro-1H-indole

The title compound were synthesized using 5-bromoindoline (1.80 g, 9.09mmol), acyl chloride (0.62 mL, 10.9 mmol), pyridine (1.10 mL, 13.6 mmol)and anhydrous THF (35 mL) to yield the crude product as grey solids. Thecrude product was used directly to next step without furtherpurification.

Step B1-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-indol-1-yl]-ethanone

To a solution of 52-1 (1.86 g, 7.75 mmol) in dioxane (31 mL) was addedbis(pinacolato)diboron (3.93 g, 15.5 mmol), Pd(dPPf)₂Cl₂ (0.57 g, 0.78mmol) and anhydrous potassium acetate (3.80 g, 38.7 mmol) under N₂. Thereaction was heated at 105° C. for 2 h. Upon cooling to roomtemperature, water (20 mL) was added to dilute, and the resultingmixture was extracted with EtOAc (3×15 mL). The combined organic layerswere washed with brine, dried over MgSO₄ and concentrated in vacuo. Thecrude product was purified by flash column chromatography on silica gel(EtOAc/n-hexane, 1:50 to 1:2) to yield a pale yellow solid. ¹H-NMR (500MHz, CDCl₃): δ 1.34 (s, 12H), 2.32 (s, 3H), 3.18 (t, J=8.4 Hz, 2H), 4.05(t, J=8.5 Hz, 2H), 7.62 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 8.19 (d, J=8.1Hz, 1H).

Step C 1-Acetyl-5-(5-fluoropyridin-3-yl)-2,3-dihydro-1H-indole

A suspension of 52-2 (150 mg, 0.52 mmol), 3-bromo-5-fluoropyridine (111mg, 0.63 mmol), sodium carbonate (277 mg, 2.61 mmol) andtetrakis(triphenylphosphine) palladium (O) (30 mg, 0.03 mmol) indimethoxyethane (9 mL) and water (3 mL) was stirred at 90° C. undernitrogen for 2 h. The reaction mixture was cooled to room temperatureslowly and then diluted with water. The aqueous layer was extracted withEtOAc and the combined organic layers were washed with brine twice anddried over MgSO₄. After evaporation in vacuo, the resulting residue waspurified by flash chromatography on silica gel (MeOH/CH₂Cl₂, 0 to 2%)and crystallization from acetone to yield colorless crystals. mp178-180° C., R_(f)=0.26 (MeOH/CH₂Cl₂, 1:20). ¹H-NMR (500 MHz, CDCl₃): δ2.26 (s, 3H), 3.28 (t, J=8.4 Hz, 2H), 4.13 (t, J=8.5 Hz, 2H), 7.40 (m,2H), 7.56 (dt, J=2.0, 9.6 Hz, 1H), 8.30 (d, J=8.2 Hz, 1H), 8.41 (d,J=1.8 Hz, 1H), 8.64 (s, 1H). ¹³C-NMR (125 MHz, CDCl₃): δ 24.2, 27.9,49.0, 117.4, 118.1, 120.7 (d, ²J_(C,F)=18.6 Hz), 123.2, 126.8, 131.5,132.3, 136.0 (d, ²J_(C,F)=23.3 Hz), 138.1 (d, ⁴J_(C,F)=3.6 Hz), 143.6(d, ⁴J_(C,F)=3.2 Hz), 159.7 (d, ¹J_(C,F)=257 Hz), 168.9. MS (ESI)m/z=257.76 [M+H]⁺.

The compounds in Table 5 were prepared using the chemistry described inExample 52.

TABLE 5 MS H¹ NMR Ex Structure IUPAC Name (M + 1) 500 MHz, CDCl₃ 53

5-(1-acetyl-2,3- dihydro-1H-indol-5- yl)pyridine-3- carbonitrile 264.83δ 2.27 (s, 3H), 3.30 (t, J = 8.4 Hz, 2H), 4.15 (t, J = 8.5 Hz, 2H), 7.40(m, 2H), 8.10 (t, J = 2.1 Hz, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.80 (d, J= 1.5 Hz, 1H), 9.00 (d, J = 2.2 Hz, 1H). 54

1-acetyl-5-(5- methoxypyridin-3- yl)-2,3-dihydro-1H- indole 269.37 δ2.25 (s, 3H), 3.27 (t, J = 8.5 Hz, 2H), 3.92 (s, 3H), 4.12 (t, J = 8.5Hz, 2H), 7.35 (t, J = 2.1 Hz, 1H), 7.40 (m, 2H), 8.26 (d, J = 2.6 Hz,1H), 8.29 (d, J = 8.3 Hz, 1H), 8.43 (d, J = 1.8 Hz, 1H). 55

1-[5-(1-acetyl-2,3- dihydro-1H-indol-5- yl)pyridin-3- yl]ethanone 281.67δ 2.26 (s, 3H), 2.69 (s, 3H), 3.29 (t, J = 8.5 Hz, 2H), 4.13 (t, J = 8.5Hz, 2H), 7.45 (m, 2H), 8.32 (t, J = 8.3 Hz, 1H), 8.38 (t, J = 2.1 Hz,1H), 8.98 (d, J = 2.0 Hz, 1H), 9.01 (s, 1H). 56

1-[5-1-acetyl-2,3- dihydro-1H-indol-5- yl)pyridin-3- yl]ethanol 283.77 δ1.53 (s, J = 6.5 Hz, 3H), 2.67 (s, 3H), 3.29 (d, J = 5.3 Hz, 2H), 4.19(d, J = 3.8 Hz, 2H), 4.98 (q, J = 6.5 Hz, 1H), 7.49 (s, 1H), 7.55 (s,1H), 8.05 (s, 1H), 8.20 (s, 1H), 8.49 (s, 1H), 8.66 (s, 1H). 57

1-acetyl-5-(5- phenylpyridin-3-yl)- 2,3-dihydro-1H- indole 315.37 δ 2.26(s, 3H), 3.29 (t, J = 8.4 Hz, 2H), 4.13 (t, J = 8.4 Hz, 2H), 7.42- 7.52(m, 5H), 7.64 (m, 2H), 8.03 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 8.3 Hz,1H), 8.79 (m, 2H). 58

1-acetyl-5-(4- methylpyridin-3-yl)- 2,3-dihydro-1H- indole 253.33 δ 2.25(s, 3H), 2.29 (s, 3H), 3.26 (t, J = 8.5 Hz, 2H), 4.12 (t, J = 8.5 Hz,2H), 7.12-7.18 (m, 3H), 8.27 (d, J = 8.2 Hz, 1H), 8.41 (m, 2H).

Assay Description and Results Methods for V79-Human-CYP11B2 andV79-Human-CYP11B1 Assays

V79 cell lines stably expressing the either the human CYP11B2 or thehuman CYP11B1 enzyme were generated using a standard transfectionprotocol. V79 cells were transfected with plasmidspTriEx3-Hygro-hCyp11B2 or pTriEx3-Hygro-hCyp11B1 using Lipofectamine2000 reagent. V79 cells that stably express the human CYP11B2 or humanCYP11B1 enzyme were selected for and maintained in DMEM supplementedwith 10% FBS and 400 μg/mL hygromycin for 2 weeks. Single cell cloneswere generated by infinite dilution in DMEM supplemented with 10% FBSand 400 μg/mL hygromycin until single colonies were obtained. ClonesV79-hCYP11B2-CLE9 and V79-hCYP11B1-CL8C7, were determined to produce themost aldosterone and cortisol, respectively, and were selected forinhibitor screening. For testing of inhibitors, cells were harvested at80% confluency with 0.05% Trypsan-EDTA, washed once in PBS, andreconstituted in DMEM+0.1% BSA media at a cell concentration of 600,000cells/mL for the CYP11B2 assay and 280,000 cells/mL for the CYP11B1assay. 25 μL of cells were added to a 384 well tissue culture treatedplate and mixed with 0.3 μL of inhibitor or DMSO (1% final DMSOconcentration) for 1 hour at 37° C., 5% CO₂. After pre-incubation withinhibitor, the reaction was initiated by adding 5 μL of substrate (finalconcentration of 125 nM 11-deoxycorticosterone for the CYP11B2 assay or250 nM 11-deoxycortisol for the CYP11B1 assay). The reaction was carriedout for 3 hours at 37° C., 5% CO₂ and was stopped by harvesting thesupernatants. The amount of product in the supernatant (aldosterone forCYP11B2 assay and cortisol for the CYP11B1 assay) was measured usingHTRF-based assay kit (Aldosterone HTRF-CisBio#64ALDPEB, CortisolHTRF-CisBio #63IDC002-CORT). IC₅₀s for the inhibitor were determined byplotting the amount of product formed against the concentration ofinhibitor using sigmoidal dose-response curve (variable slope) fit inGraphPad.

The compounds of Examples 1-20 and 35-49 were tested in theV79-Human-CYP11B2 cell assay and found to have IC₅₀s for inhibition ofhuman CYP11B2 of less than 10000 nM. A sub-group of compounds had IC₅₀sless than or equal to 250 nM, and a further sub-group of compounds hadIC₅₀s less than or equal to 50 nM.

The compounds of Examples 1-20 and 35-49 were also tested in theV79-Human-CYP11B1 cell assay. A sub-group of compounds were at least10-fold more selective for inhibition of CYP11B2 as compared to CYP11B1,and a further sub-group of compounds were at least 30-fold moreselective for inhibition of CYP11B2. Representative examples of datacollected for compounds of the present invention are shown in Table 6below.

TABLE 6 V79 Human V79 Human Exam- CYP11B2 CYP11B1 ple IUPAC Name IC₅₀(nM) IC₅₀ (nM) 1 1-(5-(5-fluoropyridin-3- 110 >10,000yl)indolin-1-yl)ethanone 43 1-(7-chloro-5-(pyridin-3- 7.4 570yl)indolin-1-yl)ethanone 2 1-(7-chloro-5-(5- 12 7,900fluoropyridine-3-yl)indolin- 1-yl)ethanone 3 1-(7-chloro-5-(5-methoxy4.1 130 pyridin-3-yl)indolin-1- yl)ethanone 7 1-(7-chloro-5-(4- 5.0 610(trifluoromethyl)pyridine-3- yl)indolin-1-yl)ethanone 105-(1-acetyl-7-chloroindolin- 35 1,600 5-yl)4-methylnicotinotrile 111-(7-chloro-5-(isoquinolin- 0.7 60 4-yl) indolin-1-yl)ethanone 61-(7-chloro-5-(5- 7.5 400 (trifluoromethyl)pyridine-3 -yl)indolin-1-yl)ethanone 4 (S)-1-(7-chloro-5-(5-(1,1,1,- 1.2 26trifluoro-2-hydroxypropan- 2-yl)pyridine-3-yl)indolin-1- yl)ethanone 5(R)-1-(7-chloro-5-(5-(1,1,1,- 2.4 53 trifluoro-2hydroxypropan-2-yl)pyridine-3-yl)indolin-1- yl)ethanone 9 1-(7-chloro-5-(4-ethyl-5- 2.3400 fluoropyridin-3-yl)indolin- 1-yl)ethanone 81-(7-chloro-5-(5-fluoro-4- 1.4 270 methylpyridin-3-yl)indolin-1-yl)ethanone 12 1-(7-fluoro-5-(pyridine-3-yl) 4.9 900 indolin-1-yl)ethanone 18 1-(7-fluoro-5-(5- 15 1,100 fluoropyridine-3-yl)indolin-1-yl)-ethanone 19 1-(7-fluoro-5-(5-fluoro-4- 1.0 100methylpyridine-3-yl)indolin- 1-yl)-ethanone 20 1-(5-(4-ethyl-5- 1.6 500fluoropyridine-3-yl)-7- fluoroindolin-1-yl)ethanone 14(R)-1-(7-fluoro-5-(5-(1,1,1- 0.8 13 trifluoro-2-hydroxypropan-2-yl)pyridin-3-yl)indolin-1- yl)ethanone 13 (S)-1-(7-fluoro-5-(5-(1,1,1-2.1 23 trifluoro-2-hydroxypropan- 2-yl)pyridin-3-yl)indolin-1-yl)ethanone 16 5-(1-acetyl-7-fluoroindolin- 97 >10,0005-yl)nicotinonitrile 17 5-(1-acetyl-7-fluoroindolin- 12 5405-yl)-4-methylnicotino nitrile 15 1-(7-fluoro-5-(4- 0.2 68methylpyridin-3-yl)indolin- 1-yl)ethanone 47 1-(6-fluoro-5-(pyridin-3-180 380 yl)indolin-1-yl)ethanone 48 1-(5-(4-ethyl-5- 690 >10,000fluoropyridin-3-yl)-6- fluoroindolin-1-yl)ethanone 49 1-(5-(4-ethyl-5-170 4,000 fluoropyridin-3-yl)-6- fluoroindolin-1-yl)ethanone 441-(6-chloro-5-(pyridin-3- 640 470 yl)indoline-1-yl)ethanone 451-(6-chloro-5-(5- 810 760 fluoropyridine-3-yl)indolin- 1-yl)ethanone 461-(6-chloro-5-(4-ethyl-5- 620 780 fluoropyridine-3-yl)indolin-1-yl)ethanone

Compounds 21-34 and 50-58 were assayed with a modified protocol from theone described above and found to have IC₅₀s for inhibition of humanCYP11B2 of less than 10000 nM. For the CYP11B2 assay, cells werereconstituted in DMEM+0.1% BSA media at a cell concentration of 600,000cells/mL and for the CYP11B1 assay cells were reconstituted in DMEM+0.1%BSA media at a cell concentration of 280,000 cells/mL. 25 μl of cellswere added to a 384 well tissue culture treated plate and mixed with0.30 of inhibitor or DMSO (1% final DMSO concentration) for 1 hour at37° C., 5% CO₂.

Representative examples of data collected for some of compounds of thepresent invention using this modified procedure are shown in Table 7below.

TABLE 7 V79 Human V79 Human Exam- CYP11B2 CYP11B1 ple IUPAC Name IC₅₀(nM) IC₅₀ (nM) 21 1-propanoyl-5-pyridin-3-yl- 228 47372,3-dihydro-1H-indole 22 1-(3-chloropropanoyl)-5- >5000 >5000pyridin-3-yl-2,3-dihydro- 1H-indole 23 1-(cyclopropylcarbonyl)-5- 12851423 pyridin-3-yl-2,3-dihydro- 1H-indole 24 1-[(4-fluorophenyl)2833 >5000 carbonyl]-5-pyridin-3-yl- 2,3-dihydro-1H-indole 251-[(4-methoxyphenyl) 1433 >5000 carbonyl]-5-pyridin-3-yl-2,3-dihydro-1H-indole 26 1-(phenylacetyl)-5-pyridin- 3070 >50003-yl-2,3-dihydro-1H-indole 27 5-pyridin-3-yl-1-(thiophen- >5000 15232-ylcarbonyl)-2,3-dihydro- 1H-indole 28 4-(1-acetyl-2,3-dihydro-1H- 0.752 indol-5-yl)isoquinoline 29 4-(1-propanoyl-2,3-dihydro- 2.8 5161H-indol-5-yl)isoquinoline 30 4-[1-(2-methylpropanoyl)- 30 37232,3-dihydro-1H-indol-5- yl]isoquinoline 31 4-[1-(cyclopropylcarbonyl)-152 6093 2,3-dihydro-1H-indol-5- yl]isoquinoline 32 1-(7-chloro-5-(5-10.6 525 fluoropyridin-3-yl)indolin- 1-yl)-2,2,2-trifluoroethanone 332,2,2-trifluoro-1-(7-fluoro- 17.4 1414 5-(5-fluoropyridin-3-yl)indolin-1-yl)ethanone 34 1-(5-(pyridin-3-yl)indolin-1- 6 3383yl)ethanethione 50 1-acetyl-5-pyridin-3-yl-1H- 23 1379 indole 514-(1-acetyl-1H-indol-5- 0.6 34 yl)isoquinoline 521-acetyl-5-(5-fluoropyridin- 61 6812 3-yl)-2,3-dihydro-1H-indole 535-(1-acetyl-2,3-dihydro-1H- 426 6642 indol-5-yl)pyridine-3- carbonitrile54 1-acetyl-5-(5- 16 803 methoxypyridin-3-yl)-2,3- dihydro-1H-indole 551-[5-(1-acetyl-2,3-dihydro- 36 3125 1H-indol-5-yl)pyridin-3- yl]ethanone56 1-[5-(1-acetyl-2,3-dihydro- 55 3756 1H-indol-5-yl)pyridin-3-yl]ethanol 57 1-acetyl-5-(5-phenylpyridin- 3.0 1603-yl)-2,3-dihydro-1H-indole 58 1-acetyl-5-(4-methylpyridin- 2.2 3663-yl)-2,3-dihydro-1H-indole

While the invention has been described with reference to certainparticular embodiments thereof, numerous alternative embodiments will beapparent to those skilled in the art from the teachings describedherein. Recitation or depiction of a specific compound in the claims(i.e., a species) without a specific stereoconfiguration designation, orwith such a designation for less than all chiral centers, is intended toencompass the racemate, racemic mixtures, each individual enantiomer, adiastereoisomeric mixture and each individual diastereomer of thecompound where such forms are possible due to the presence of one ormore asymmetric centers. All patents, patent applications andpublications cited herein are incorporated by reference in theirentirety.

1. A compound of the formula

or a pharmaceutically acceptable salt thereof wherein: R¹ is —C(O)R⁷;—C(O)OR⁷; —C(O)N(R¹¹)(R¹²); —C(S)R⁷; —S(O)₂R⁷; alkyl which is optionallysubstituted one or more times by halogen; cycloalkyl, which isoptionally substituted one or more times by halogen, alkyl or haloalkyl;aryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; arylalkyl,wherein the aryl ring is optionally substituted one or more times byhalogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;heteroaryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; orarylalkylcarbonyl, wherein the aryl ring is optionally substituted oneor more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; R² is H; halogen; —CN; —OR⁷;—N(R¹⁰)C(O)R⁷; —NR¹¹R¹²; —C(O)R⁷; —C(O)N(R¹¹)(R¹²); —N(R¹⁰)C(O)—R⁷;—C(O)OR⁷; —OC(O)R⁷; —SO₂N(R¹¹)(R¹²); —N(R¹⁰)SO₂—R⁷; —S(O)_(m)—R⁷; alkyloptionally substituted one or more times by halogen, —OR⁷, NR⁸R⁹, —CN,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷,—SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; cycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷,—NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)R⁷; heterocycloalkyl optionally substitutedone or more times by halogen, alkyl, haloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; aryl optionally substituted one or moretimes by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷,—SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or heteroaryl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl,—OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷,—OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; R³ is H;halogen; —CN; —OR⁷; —N(R¹⁰)C(O)R⁷; —NR¹¹R¹²; —C(O)R⁷; —C(O)N(R¹¹)(R¹²);—N(R¹⁰)C(O)—R⁷; —C(O)OR⁷; —OC(O)R⁷; —SO₂N(R¹¹)(R¹²); —N(R¹⁰)SO₂—R⁷;—S(O)_(m)—R⁷; alkyl optionally substituted one or more times by halogen,—OR⁷, NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷,—OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; cycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,—NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionally substitutedone or more times by halogen, alkyl, haloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; aryl optionally substituted one or moretimes by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷,—SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or heteroaryl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl,—OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷,—OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; R⁴ is H;halogen; —CN; alkyl optionally substituted one or more times by halogenor cycloalkyl optionally substituted once or twice by alkyl or halogen;or cycloalkyl optionally substituted once or twice by alkyl or halogen;R⁵ is H; halogen; —CN; alkyl optionally substituted one or more times byhalogen or cycloalkyl optionally substituted once or twice by alkyl orhalogen; or cycloalkyl optionally substituted once or twice by alkyl orhalogen; R⁶ is H; halogen; —CN; alkyl optionally substituted one or moretimes by halogen or cycloalkyl optionally substituted once or twice byalkyl or halogen; or cycloalkyl optionally substituted once or twice byalkyl or halogen; R⁷ is independently H; alkyl optionally substitutedone or more times by halogen, —OR¹⁰, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰,—C(O)N(R⁸)(R⁹), —C(O)R¹⁰, —C(O)OR¹⁰ or —S(O)_(m)—R¹⁰; cycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,—OR¹⁰, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or—S(O)_(m)—R¹⁰; aryl optionally substituted one or more times by halogen,alkyl, haloalkyl, cycloalkyl, —OR¹⁰, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰,—C(O)N(R⁸)(R⁹), —C(O)R¹⁰, —C(O)OR¹⁰—OC(O)R¹⁰, or —S(O)_(m)—R¹⁰; orheteroaryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR¹⁰, —NR⁸R⁹, —CN, —N(R⁹)C(O)R¹⁰,—C(O)N(R⁸)(R⁹), —C(O)R¹⁰, —C(O)OR¹⁰—OC(O)R¹⁰ or —S(O)_(m)—R¹⁰; R⁸ isindependently H or alkyl; R⁹ is independently H or alkyl; or R⁸ and R⁹are joined together with the nitrogen to which they are attached form asaturated 5- to 7-membered heterocyclic ring; R¹⁰ is independently H,alkyl or haloalkyl; R¹¹ is independently H; alkyl optionally substitutedone or more times by halogen, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷ or —S(O)_(m)—R⁷; cycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷,—NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁸ or —S(O)_(m)—R⁸;aryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁷)(R⁸),—C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷ or—S(O)_(m)—R⁷; or heteroaryl optionally substituted one or more times byhalogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷ or —S(O)_(m)—R⁷; R¹² isindependently H; alkyl optionally substituted one or more times byhalogen, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷,—C(O)OR⁷ or —S(O)_(m)—R⁷; cycloalkyl optionally substituted one or moretimes by halogen, alkyl, haloalkyl, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁸ or —S(O)_(m)—R⁸; aryl optionally substitutedone or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁷)(R⁸), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷ or—S(O)_(m)—R⁷; heterocycloalkyl optionally substituted one or more timesby halogen, alkyl, haloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷ or —S(O)_(m)—R⁷; orheteroaryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷ or —S(O)_(m)—R⁷; or R¹¹ and R¹² are joinedtogether with the nitrogen to which they are attached form a saturated5- to 7-membered heterocyclic ring; R¹³ is H; halogen; —CN; —OR⁷;—NR¹¹R¹²; —N(R¹⁰)C(O)R⁷; —C(O)N(R¹¹)(R¹²); —C(O)R⁷; —C(O)OR⁷; —OC(O)R⁷;—SO₂N(R¹¹)(R¹²); —N(R¹⁰)SO₂—R⁷; —S(O)_(m)—R⁷; alkyl optionallysubstituted one or more times by halogen, —OR⁷, —NR⁸R⁹, —CN,—N(R¹¹)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷, or —S(O)_(n)—R⁷; cycloalkyl optionally substituted one ormore times by halogen, alkyl, haloalkyl, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;aryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁸)(R⁹),—C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or—S(O)_(m)—R⁷; heterocycloalkyl optionally substituted one or more timesby halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or monocyclic heteroaryl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl,—OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; R¹⁴ is H; halogen; —CN;—OR⁷; —NR¹¹R¹²; —N(R¹⁰)C(O)R⁷; —C(O)N(R¹¹)(R¹²); —C(O)R⁷; —C(O)OR⁷;—OC(O)R⁷; —SO₂N(R¹¹)(R¹²); —N(R¹⁰)SO₂—R⁷; —S(O)_(m)—R⁷; alkyl optionallysubstituted one or more times by halogen, —OR⁷, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷,—SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; cycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷,—NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; aryl optionally substituted one or moretimes (e.g., 1 to 4 times) by halogen, alkyl, haloalkyl, cycloalkyl,—OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁷)(R⁸), —C(O)R⁷, —C(O)OR⁷,—OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; heterocycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,—OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or monocyclic heteroaryl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl,—OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or R¹³ and R¹⁴ are joinedtogether to form a 5-7 membered carbocyclic or heterocyclic ring that isfused to the pyridyl ring to which R¹³ and R¹⁴ are attached, wherein thering formed by R¹³ and R¹⁴ is optionally substituted by 1 to 3 R¹⁵; R¹⁵is independently H; halogen; —CN; —OR⁷; —C(O)N(R⁸)(R⁹); —C(O)R⁷;—C(O)OR⁷; —OC(O)R⁷; —SO₂N(R⁸)(R⁹); —N(R¹⁹)SO₂—R⁷; —S(O)_(m)—R⁷; alkyloptionally substituted one or more times by halogen, —OR⁷, —NR⁸R⁹, —CN,—N(R¹¹)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷,—SO₂N(R⁸)(R⁹), —N(R¹⁰)S(O)₂—R⁷, or —S(O)_(m)—R⁷; cycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷,—NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁸, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; aryl optionally substituted one or moretimes by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹,—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁸)(R⁹), —C(O)R⁷—C(O)OR⁷, —OC(O)R⁷,—SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷, or —S(O)_(m)—R⁷; heterocycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷,—C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; orheteroaryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or—S(O)_(m)—R⁷;

is a single or double bond; and m is 0, 1 or 2; provided that when R¹ isbenzyl or —C(O)alkyl, R⁵, R⁶ R¹³ and R¹⁴ cannot all be hydrogen at thesame time and further provided that monocyclic heteroaryl cannot be atetrazole ring.
 2. The compound as defined in claim 1 or apharmaceutically acceptable salt thereof, wherein: R¹ is —C(O)R⁷,—C(O)OR⁷, —C(O)N(R¹¹)(R¹²), —C(S)—R⁷ or benzoyl, which is optionallysubstituted once or twice by alkyl, halogen, alkoxy or haloalkyl; R² isH; R³ is H; R⁴ is H; R⁵ is H or halogen; R⁶ is H or halogen; R⁷ is H,alkyl, haloalkyl, cycloalkyl or phenyl optionally substituted once ortwice by halogen, —OH, alkoxy or haloalkoxy, or heteroaryl; R¹¹ is H;R¹² is alkyl, phenyl or phenyl substituted one or twice by halogen, OH,alkoxy or haloalkoxy; R¹³ is i.) H, halogen, —CN, alkyl, —OR⁷,haloalkyl, hydroxyl-substituted alkyl, —C(O)R⁷ or phenyl optionallysubstituted by halogen or haloalkyl; or ii.) a group of the formula:

where: R^(a) is H, OH, or —C₁-C₃-alkyl optionally substituted with 1 to3-F; R^(b) is H, —OH, or —C₁-C₃-alkyl optionally substituted with 1 to3-F; R^(c) is —C₁-C₃-alkyl optionally substituted with 1 to 3-F; and R¹⁴is H, alkyl or haloalkyl; or R¹³ and R¹⁴ are joined together with thepyridine ring to which they are attached form

where: R¹⁵ is alkyl or halogen; and a is 0, 1 or
 2. 3. The compound asdefined in claim 1 or a pharmaceutically acceptable salt thereof, whichhas the structural formula

wherein: R¹ is —C(O)R⁷; R⁶ is halogen R⁷ is alkyl, haloalkyl, phenyl orphenyl substituted one or twice by halogen, —OH, alkoxy or haloalkoxy;R¹³ is i.) H, halogen, —CN, alkyl, —OR⁷, haloalkyl or phenyl optionallysubstituted by halogen or haloalkyl; or ii.) a group of the formula:

where: R^(a) is H, OH, or —C₁-C₃-alkyl optionally substituted with 1 to3-F; R^(b) is H, —OH, or —C₁-C₃-alkyl optionally substituted with 1 to3-F; R^(c) is —C₁-C₃-alkyl optionally substituted with 1 to 3-F; and R¹⁴is H, alkyl or haloalkyl.
 4. The compound as defined in claim 1 or apharmaceutically acceptable salt thereof, which has the structuralformula

wherein: R¹ is —C(O)R⁷; R⁵ is halogen R⁷ is alkyl, haloalkyl, phenyl orphenyl substituted one or twice by halogen, —OH, alkoxy or haloalkoxy;R¹³ is i.) H, halogen, —CN, alkyl, —OR⁷, haloalkyl or phenyl optionallysubstituted by halogen or haloalkyl; or ii.) a group of the formula:

where: R^(a) is H, OH, or —C₁-C₃-alkyl optionally substituted with 1 to3-F; R^(b) is H, —OH, or —C₁-C₃-alkyl optionally substituted with 1 to3-F; R^(c) is —C₁-C₃-alkyl optionally substituted with 1 to 3-F; and R¹⁴is H, alkyl or haloalkyl.
 5. The compound as defined in claim 1 or apharmaceutically acceptable salt thereof, which has the structuralformula

wherein: R¹ is —C(O)OR⁷ or —C(O)N(R¹¹)(R¹²), wherein R⁷, R¹¹ or R¹² isas defined as in Formula I R⁷ is alkyl, phenyl or phenyl substituted oneor twice by halogen, —OH, alkoxy or haloalkoxy; R¹¹ is H or haloalkyl;R¹² is alkyl, haloalkyl, phenyl or phenyl substituted one or twice byhalogen, OH alkoxy or haloalkoxy R¹³ is H, halogen, —CN, alkyl, —OH,—OR⁷, haloalkyl or phenyl optionally substituted by halogen orhaloalkyl; R¹⁴ is H or alkyl.
 6. The compound as defined in claim 1 or apharmaceutically acceptable salt thereof, which has the structuralformula

wherein R¹ is C(O)R⁷ or C(S)R⁷ or benzoyl, which is optionallysubstituted once or twice by alkyl, halogen, alkoxy or haloalkyl; R⁷ isalkyl, haloalkyl, cycloalkyl, phenyl, phenyl substituted once or twiceby halogen or alkoxy, or heteroaryl; R¹³ is H, —CN, alkoxy, halogen,hydroxy-substituted alkyl, phenyl or C(O)-alkyl; and R¹⁴ is H, alkyl orhalogen.
 7. The compound as defined in claim 1 or a pharmaceuticallyacceptable salt thereof, which has the structural formula

wherein: R¹ is —C(O)R⁷; R⁶ is H or halogen; R⁷ is alkyl, haloalkyl,phenyl or phenyl substituted one or twice by halogen, —OH, alkoxy orhaloalkoxy; R¹⁵ is alkyl or halogen; and a is 0, 1 or
 2. 8. The compoundas defined in claim 1 or a pharmaceutically acceptable salt thereof,which has the structural formula

wherein R¹ is —C(O)R⁷, —C(S)R⁷ or benzoyl, which is optionallysubstituted once or twice by alkyl, halogen, alkoxy or haloalkyl; R⁷ isalkyl, haloalkyl, cycloalkyl, phenyl, phenyl substituted once or twiceby halogen or alkoxy; R¹⁵ is alkyl or halo; and a is 0, 1 or
 2. 9. Acompound selected from the group consisting of:1-propanoyl-5-pyridin-3-yl-2,3-dihydro-1H-indole;1-(3-chloropropanoyl)-5-pyridin-3-yl-2,3-dihydro-1H-indole;1-(cyclopropylcarbonyl)-5-pyridin-3-yl-2,3-dihydro-1H-indole;1-[(4-fluorophenyl)carbonyl]-5-pyridin-3-yl-2,3-dihydro-1H-indole1-[(4-fluorophenyl)carbonyl]-5-pyridin-3-yl-2,3-dihydro-1H-indole;1-[(4-methoxyphenyl)carbonyl]-5-pyridin-3-yl-2,3-dihydro-1H-indole;1-(phenylacetyl)-5-pyridin-3-yl-2,3-dihydro-1H-indole;5-pyridin-3-yl-1-(thiophen-2-ylcarbonyl)-2,3-dihydro-1H-indole;4-(1-acetyl-2,3-dihydro-1H-indol-5-yl)isoquinoline;4-(1-propanoyl-2,3-dihydro-1H-indol-5-yl)isoquinoline;4-[1-(2-methylpropanoyl)-2,3-dihydro-1H-indol-5-yl]isoquinoline;4-[1-(cyclopropylcarbonyl)-2,3-dihydro-1H-indol-5-yl]isoquinoline;1-(5-(pyridin-3-yl)indolin-1-yl)ethanethione;1-acetyl-5-pyridin-3-yl-1H-indole;4-(1-acetyl-1H-indol-5-yl)isoquinoline;1-acetyl-5-(5-fluoropyridin-3-yl)-2,3-dihydro-1H-indole;5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)pyridine-3-carbonitrile;1-acetyl-5-(5-methoxypyridin-3-yl)-2,3-dihydro-1H-indole;1-[5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)pyridin-3-yl]ethanone;1-[5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)pyridin-3-yl]ethanol;1-acetyl-5-(5-phenylpyridin-3-yl)-2,3-dihydro-1H-indole;1-acetyl-5-(4-methylpyridin-3-yl)-2,3-dihydro-1H-indole; or apharmaceutically acceptable salt thereof.
 10. A compound selected fromthe group consisting of:1-(7-chloro-5-(5-fluoropyridin-3-yl)indolin-1-yl)-2,2,2-trifluoroethanone;2,2,2-trifluoro-1-(7-fluoro-5-(5-fluoropyridin-3-yl)indolin-1-yl)ethanone;or a pharmaceutically acceptable salt thereof.
 11. A pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound of Formula I as defined in claim 1 or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.
 12. Apharmaceutical composition comprising a therapeutically effective amountof at least one compound of Formula I as defined in claim 1 or apharmaceutically acceptable salt thereof, a therapeutically effectiveamount of at least one additional therapeutic agent and apharmaceutically acceptable carrier.
 13. A method for the treatment,amelioration or prevention of one or more conditions associated withinhibiting CYP11B2, which comprises administering a therapeuticallyeffective amount at least one compound of Formula I as defined in claim1 or a pharmaceutically acceptable salt thereof to a mammal in need ofsuch treatment.
 14. The method according to claim 9 wherein theconditions that could be treated ameliorated or prevented by inhibitingCYP11B2 are hypertension, heart failure such as congestive heartfailure, diastolic dysfunction, left ventricular diastolic dysfunction,heart failure, diastolic dysfunction, left ventricular diastolicdysfunction, diastolic heart failure, systolic dysfunction, hypokalemia,renal failure, restenosis, syndrome X, nephropathy, post-myocardialinfarction, coronary heart diseases, increased formation of collagen,fibrosis and remodeling following hypertension and endothelialdysfunction, cardiovascular diseases, renal dysfunction, liver diseases,vascular diseases, cerebrovascular diseases, retinopathy, neuropathy,insulinopathy, endothelial dysfunction, ischemia, myocardial andvascular fibrosis, myocardial necrotic lesions, vascular damage,myocardial necrotic lesions, vascular damage, myocardial infarction,left ventricular hypertrophy, cardiac lesions, vascular wallhypertrophy, endothelial thickening or fibrinoid necrosis of coronaryarteries.
 15. A method for inhibiting CYP11B2 in a mammal in needthereof, which comprises administering an effective amount of a compoundof the formula

or a pharmaceutically acceptable salt thereof wherein: R¹ is —C(O)R⁷;—C(O)OR⁷; —C(O)N(R¹¹)(R¹²); —C(S)R⁷; —S(O)₂R⁷; alkyl which is optionallysubstituted on or more times by halogen; cycloalkyl, which is optionallysubstituted one or more times by halogen, alkyl or haloalkyl; aryloptionally substituted one or more times by halogen, alkyl, haloalkyl,cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; arylalkyl, wherein thearyl ring is optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; heteroaryloptionally substituted one or more times by halogen, alkyl, haloalkyl,cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; arylalkylcarbonyl, whereinthe aryl ring is optionally substituted one or more times by halogen,alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;R² is H; halogen; —CN; —OR⁷; —N(R¹⁰)C(O)R⁷; —NR¹¹R¹²; —C(O)R⁷;—C(O)N(R¹¹)(R¹²); —N(R¹⁰)C(O)—R⁷; —C(O)OR⁷; —OC(O)R⁷; —SO₂N(R¹¹)(R¹²);—N(R¹⁰)SO₂—R⁷; —S(O)_(m)R⁷; alkyl optionally substituted one or moretimes by halogen, —OR⁷, NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or—S(O)_(m)—R⁷; cycloalkyl optionally substituted one or more times byhalogen, alkyl, haloalkyl, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;heterocycloalkyl optionally substituted one or more times by halogen,alkyl, haloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; aryl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl,—OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷,—OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or heteroaryloptionally substituted one or more times by halogen, alkyl, haloalkyl,cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷,—C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; R³ isH; halogen; —CN; —OR⁷; —N(R¹⁰)C(O)R⁷; —NR¹¹R¹²; —C(O)R⁷;—C(O)N(R¹¹)(R¹²); —N(R¹⁰)C(O)—R⁷; —C(O)OR⁷; —OC(O)R⁷; —SO₂N(R¹¹)(R¹²);—N(R¹⁰)SO₂—R⁷; —S(O)_(m)—R⁷; alkyl optionally substituted one or moretimes by halogen, —OR⁷, NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or—S(O)_(m)—R⁷; cycloalkyl optionally substituted one or more times byhalogen, alkyl, haloalkyl, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷;heterocycloalkyl optionally substituted one or more times by halogen,alkyl, haloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; aryl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl,—OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷,—OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or heteroaryloptionally substituted one or more times by halogen, alkyl, haloalkyl,cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷,—C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; R⁴ isH; halogen; —CN; alkyl optionally substituted one or more times byhalogen or cycloalkyl optionally substituted once or twice by alkyl orhalogen; or cycloalkyl optionally substituted once or twice by alkyl orhalogen; R⁵ is H; halogen; —CN; alkyl optionally substituted one or moretimes by halogen or cycloalkyl optionally substituted once or twice byalkyl or halogen; or cycloalkyl optionally substituted once or twice byalkyl or halogen; R⁶ is H; halogen; —CN; alkyl optionally substitutedone or more times by halogen or cycloalkyl optionally substituted onceor twice by alkyl or halogen; or cycloalkyl optionally substituted onceor twice by alkyl or halogen; R⁷ is independently H; alkyl optionallysubstituted one or more times by halogen, —OR¹⁰, —NR⁸R⁹, —CN,N(R¹⁰)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)R¹⁰, —C(O)OR¹⁰ or —S(O)_(m)—R¹⁰;cycloalkyl optionally substituted one or more times by halogen, alkyl,haloalkyl, —OR¹⁰, —NR⁸R⁹, —CN, N(R¹⁰)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰or —S(O)_(m)—R¹⁰; aryl optionally substituted one or more times byhalogen, alkyl, haloalkyl, cycloalkyl, —OR¹⁰, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)R¹⁰, —C(O)OR¹⁰—OC(O)R¹⁰, or—S(O)_(m)—R¹⁰; or heteroaryl optionally substituted one or more times byhalogen, alkyl, haloalkyl, cycloalkyl, —OR¹⁰, —NR⁸R⁹, —CN, N(R⁹)C(O)R¹⁰,—C(O)N(R⁸)(R⁹), —C(O)R¹⁰, —C(O)OR¹⁰—OC(O)R¹⁰ or —S(O)_(m)—R¹⁰; R⁸ isindependently H or alkyl; R⁹ is independently H or alkyl; or R⁸ and R⁹are joined together with the nitrogen to which they are attached form asaturated 5- to 7-membered heterocyclic ring; R¹⁰ is independently H,alkyl or haloalkyl; R¹¹ is independently H; alkyl optionally substitutedone or more times by halogen, —OR⁷, —NR⁸R⁹, —CN, N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷ or —S(O)_(m)—R⁷; cycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷,—NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁸ or —S(O)_(m)—R⁸;aryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹)—N(R¹⁰)C(O)(R⁷),—C(O)N(R⁷)(R⁸), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷ or —S(O)_(m)—R⁷;heterocycloalkyl optionally substituted one or more times by halogen,alkyl, haloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷ or —S(O)_(m)—R⁷; or heteroaryl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl,—OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷,—OC(O)R⁷ or —S(O)_(m)—R⁷; R¹² is independently H; alkyl optionallysubstituted one or more times by halogen, —OR⁷, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷ or —S(O)_(m)—R⁷;cycloalkyl optionally substituted one or more times by halogen, alkyl,haloalkyl, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁸ or—S(O)_(m)—R⁸; aryl optionally substituted one or more times by halogen,alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷),—C(O)N(R⁷)(R⁸), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷ or —S(O)_(m)—R⁷;heterocycloalkyl optionally substituted one or more times by halogen,alkyl, haloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷ or —S(O)_(m)—R⁷; or heteroaryl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl,—OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷,—OC(O)R⁷ or —S(O)_(m)—R⁷; or R¹¹ and R¹² are joined together with thenitrogen to which they are attached form a saturated 5- to 7-memberedheterocyclic ring; R¹³ is H; halogen; —CN; —OR⁷; —NR¹¹R¹²;—N(R¹⁰)C(O)R⁷; —C(O)N(R¹¹)(R¹²); —C(O)R⁷; —C(O)OR⁷; —OC(O)R⁷;—SO₂N(R¹¹)(R¹²); —N(R¹⁰)SO₂—R⁷; —S(O)_(m)—R⁷; alkyl optionallysubstituted one or more times by halogen, —OR⁷, —NR⁸R⁹, —CN,—N(R¹¹)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷, or —S(O)_(m)—R⁷; cycloalkyl optionally substituted one ormore times by halogen, alkyl, haloalkyl, —OR⁷, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or—S(O)_(m)—R⁷; aryl optionally substituted one or more times by halogen,alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷),—C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionally substitutedone or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or monocyclic heteroaryl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl,—OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; R¹⁴ is H; halogen; —CN;—OR⁷; —NR¹¹R¹²; —N(R¹⁹)C(O)R⁷; —C(O)N(R¹¹)(R¹²); —C(O)R⁷; —C(O)OR⁷;—OC(O)R⁷; —SO₂N(R¹¹)(R¹²); —N(R¹⁰)SO₂—R⁷; —S(O)_(m)—R⁷; alkyl optionallysubstituted one or more times by halogen, —OR⁷, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷,—SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; cycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷,—NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; aryl optionally substituted one or moretimes (e.g., 1 to 4 times) by halogen, alkyl, haloalkyl, cycloalkyl,—OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁷)(R⁸), —C(O)R⁷, —C(O)OR⁷,—OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; heterocycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,—OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or monocyclic heteroaryl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl,—OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; or R¹³ and R¹⁴ are joinedtogether to form a 5-7 membered carbocyclic or heterocyclic ring that isfused to the pyridyl ring to which R¹³ and R¹⁴ are attached, wherein thering formed by R¹³ and R¹⁴ is optionally substituted by 1 to 3 R¹⁵; R¹⁵is independently H; halogen; —CN; —OR⁷; —C(O)N(R⁸)(R⁹); —C(O)R⁷;—C(O)OR⁷; —OC(O)R⁷; —SO₂N(R⁸)(R⁹); —N(R¹⁹)SO₂—R⁷; —S(O)_(m)—R⁷; alkyloptionally substituted one or more times by halogen, —OR⁷, —NR⁸R⁹, —CN,—N(R¹¹)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷,—SO₂N(R⁸)(R⁹), —N(R¹⁰)S(O)₂—R⁷, or —S(O)_(m)—R⁷; cycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷,—NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁸, —SO₂N(R⁸)(R⁹),—N(R¹⁰)SO₂—R⁷ or —S(O)_(m)—R⁷; aryl optionally substituted one or moretimes by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹,—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁸)(R⁹), —C(O)R⁷—C(O)OR⁷, —OC(O)R⁷,—SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷, or —S(O)_(m)—R⁷; heterocycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)R⁷,—C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or —S(O)_(m)R⁷; orheteroaryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷, —SO₂N(R⁸)(R⁹), —N(R¹⁰)SO₂—R⁷ or—S(O)_(m)—R⁷;

is a single or double bond; and m is 0, 1 or 2; provided that when R¹ is—C(O)alkyl, R⁵, R⁶ R¹³ and R¹⁴ cannot all be hydrogen at the same timeand further provided that monocyclic heteroaryl cannot be a tetrazolering.